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Clinical Trial Results:
Multi-center, double-blind, randomised, placebo-controlled, phase IIb dose-finding study to evaluate efficacy and safety of different subcutaneous doses of BI 655130 in patients with moderate to severe Palmoplantar Pustulosis (PPP)

Summary
EudraCT number	2018-003078-28
Trial protocol	BE DE FR CZ PL GB
Global end of trial date	28 Jul 2021

Results information
Results version number	v1(current)
This version publication date	17 Jul 2022
First version publication date	17 Jul 2022
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

1368-0016

ISRCTN number

US NCT number

NCT04015518

WHO universal trial number (UTN)

Sponsor organisation name

Boehringer Ingelheim

Sponsor organisation address

Binger Strasse 173, Ingelheim am Rhein, Germany, 55216

Public contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, clintriage.rdg@boehringer-ingelheim.com

Scientific contact

Boehringer Ingelheim, Call Center, Boehringer Ingelheim, 001 18002430127, 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

16 Sep 2021

Is this the analysis of the primary completion data?

Yes

Primary completion date

06 Aug 2020

Global end of trial reached?

Yes

Global end of trial date

28 Jul 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to provide dose-ranging data for 4 dose regimens of spesolimab (with each regimen consisting of a loading and a separate maintenance subcutaneous dose) compared to placebo on the primary endpoint of percentage change from baseline in PPP Area and Severity Index (PPP ASI) at Week 16. Supportive dose-ranging assessments were done on pre-specified secondary endpoints.

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 subjects as required.

Background therapy

Evidence for comparator

Actual start date of recruitment

26 Aug 2019

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 7

Country: Number of subjects enrolled

Belgium: 4

Country: Number of subjects enrolled

Canada: 11

Country: Number of subjects enrolled

Czechia: 4

Country: Number of subjects enrolled

France: 12

Country: Number of subjects enrolled

Germany: 19

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

Japan: 65

Country: Number of subjects enrolled

Korea, Republic of: 8

Country: Number of subjects enrolled

Netherlands: 2

Country: Number of subjects enrolled

Poland: 19

Country: Number of subjects enrolled

Russian Federation: 10

Country: Number of subjects enrolled

Taiwan: 3

Country: Number of subjects enrolled

United Kingdom: 3

Country: Number of subjects enrolled

United States: 25

Worldwide total number of subjects

200

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)

163

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This was a randomised, placebo-controlled, double-blind, parallel-design trial comparing 5 treatment arms over 52 weeks. Randomisation was stratified for Japan versus non-Japan. Patients who completed the treatment period, per investigator judgement, could continue treatment with spesolimab in the open-label extension trial 1368-0024.

Screening details

All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo & Spesolimab

Arm description

Subcutaneous injections of placebo matching Spesolimab, with subcutaneous injections of Spesolimab starting at week 16, for a total treatment time of 52 weeks.

Arm type

Placebo

Investigational medicinal product name

Placebo matching Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of placebo matching Spesolimab until Week 16.

Investigational medicinal product name

Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of Spesolimab starting at week 16, for a total treatment time until week 52.

Spesolimab ‘Speso Low’

Arm description

Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks.

Spesolimab ‘Speso Medium-low’

Arm description

Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks.

Spesolimab ‘Speso Medium-high’

Arm description

Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks.

Spesolimab ‘Speso High’

Arm description

Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Arm type

Experimental

Investigational medicinal product name

Spesolimab

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Number of subjects in period 1 ^[1]	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Started	43	22	21	22	44
Full analysis set (FAS)	43	22	21	22	44
Completed	32	19	18	17	32
Not completed	11	3	3	5	12
Personal reasons	1	-	-	-	1
Could not keep appointments due to work	1	-	-	-	-
Prostate carcinoma	1	-	-	-	-
Patient wants to discontinue treatment	-	-	-	1	-
Patient did not come for consecutive visits	-	1	-	-	-
Withdrew consent	1	-	-	-	-
Difficult for patient to come to the hospital	-	-	-	-	1
Consent withdrawn by subject	-	1	-	1	1
not willing to travel due to Covid-19	-	-	1	-	-
Adverse event, non-fatal	6	1	1	3	3
Pregnancy	-	-	-	-	1
Lost to follow-up	-	-	-	-	1
Lack of efficacy	1	-	1	-	4

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: Out of the 200 screened subjects 152 subjects were randomized and treated.

Baseline characteristics

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Reporting group title

Placebo & Spesolimab

Reporting group description

Subcutaneous injections of placebo matching Spesolimab, with subcutaneous injections of Spesolimab starting at week 16, for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Low’

Reporting group description

Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Medium-low’

Reporting group description

Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Medium-high’

Reporting group description

Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso High’

Reporting group description

Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Reporting group values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’	Total
Number of subjects	43	22	21	22	44	152
Age categorical
Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: Subjects
In utero	0	0	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0	0	0
Newborns (0-27 days)	0	0	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0	0	0
Children (2-11 years)	0	0	0	0	0	0
Adolescents (12-17 years)	0	0	0	0	0	0
Adults (18-64 years)	32	18	21	19	35	125
From 65-84 years	11	4	0	3	9	27
85 years and over	0	0	0	0	0	0
Age Continuous
Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: years
arithmetic mean (standard deviation)	57.7 ( 10.1 )	54.2 ( 12.3 )	51.6 ( 7.9 )	52.8 ( 9.2 )	53.4 ( 13.0 )	-
Sex: Female, Male
Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: Participants
Female	35	15	16	17	27	110
Male	8	7	5	5	17	42
Race (NIH/OMB)
Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: Subjects
American Indian or Alaska Native	0	0	0	0	0	0
Asian	18	9	9	9	15	60
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0
Black or African American	1	0	0	0	0	1
White	21	11	10	12	26	80
More than one race	0	0	0	0	0	0
Unknown or Not Reported	3	2	2	1	3	11
Ethnicity (NIH/OMB)
Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: Subjects
Hispanic or Latino	0	0	0	0	0	0
Not Hispanic or Latino	40	20	19	21	41	141
Unknown or Not Reported	3	2	2	1	3	11
Palmoplantar Pustulosis Area and Severity Index (PPP ASI)
The PPP ASI is an investigator assessment of the extent and severity of pustular and plaque lesions on the palms and soles presenting in PPP patients. This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 (best) to 72 (worst). It is a linear combination of the percent of surface area of skin that is affected on the palms and soles of the body and the severity of erythema, pustules, and scaling (desquamation). Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.
Units: Score on a scale
arithmetic mean (standard deviation)	27.07 ( 12.44 )	23.85 ( 9.42 )	23.62 ( 11.02 )	26.65 ( 11.20 )	24.00 ( 10.25 )	-

End points

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Reporting group title

Placebo & Spesolimab

Reporting group description

Subcutaneous injections of placebo matching Spesolimab, with subcutaneous injections of Spesolimab starting at week 16, for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Low’

Reporting group description

Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Medium-low’

Reporting group description

Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso Medium-high’

Reporting group description

Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks.

Reporting group title

Spesolimab ‘Speso High’

Reporting group description

Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Primary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

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End point title

The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

End point description

PPP ASI is a tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 (best) to 72 (worst). It is a linear combination of the percent of surface area of skin that is affected on the palms and soles of the body and the severity of erythema, pustules, and scaling (desquamation): Percent change from baseline is calculated as (PPP ASI current - PPP ASI baseline) / PPP ASI baseline * 100%. LS means, differences and confidence intervals were estimated by (Restricted maximum likelihood) based MMRM with fixed, categorical effects of treatment at each visit, region and continuous effect of baseline at each visit as well as random effects of subject. Values post rescue medication or 6 weeks following last study treatment before discontinuation were censored. Unstructured covariance matrix was used. Full Analysis Set (FAS): all patients who were randomised and received at least one dose of study drug. Only subjects with non-missing endpoint data were included.

End point type

Primary

End point timeframe

week 0 (baseline) and week 16

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	38	20	21	20	41
Units: Percentage of change in PPP ASI
least squares mean (confidence interval 95%)	-33.6 (-43.5 to -23.7)	-44.2 (-57.8 to -30.6)	-48.3 (-61.8 to -34.7)	-46.2 (-59.9 to -32.6)	-38.9 (-48.5 to -29.3)

Statistical analysis 1

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[1]

P-value

= 0.2179

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-10.5

Confidence interval

level

95%

sides

2-sided

lower limit

-27.4

upper limit

6.3

Variability estimate

Standard error of the mean

Dispersion value

8.5

Notes
[1] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 2

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[2]

P-value

= 0.0883

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-14.6

Confidence interval

level

95%

sides

2-sided

lower limit

-31.5

upper limit

2.2

Variability estimate

Standard error of the mean

Dispersion value

8.5

Notes
[2] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 3

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

= 0.1414

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-12.6

Confidence interval

level

95%

sides

2-sided

lower limit

-29.4

upper limit

4.3

Variability estimate

Standard error of the mean

Dispersion value

8.5

Notes
[3] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 4

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[4]

P-value

= 0.4514

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-19.1

upper limit

8.6

Variability estimate

Standard error of the mean

Dispersion value

Notes
[4] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 5

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the Multiple Comparison Procedure - Modelling (MCP-Mod) approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05).

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[5]

P-value

= 0.212 ^[6]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[5] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.
[6] - Adjusted for multiplicity.

Statistical analysis 6

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[7]

P-value

= 0.1057 ^[8]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[7] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 70% of the maximum effect was achieved at the “low dose” regimen.
[8] - Adjusted for multiplicity.

Statistical analysis 7

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[9]

P-value

= 0.5241 ^[10]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[9] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 25% of the maximum effect was achieved at the “medium-low dose” regimen.
[10] - Adjusted for multiplicity.

Statistical analysis 8

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[11]

P-value

= 0.2773 ^[12]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[11] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 20% of maximum effect was achieved at the “low dose”, 95% of maximum effect was achieved at “medium high dose”.
[12] - Adjusted for multiplicity.

Statistical analysis 9

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[13]

P-value

= 0.3867 ^[14]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[13] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.
[14] - Adjusted for multiplicity.

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

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End point title

Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

End point description

Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4. The PPP Pain VAS is a unidimensional measure of pain intensity due to palmoplantar pustulosis on palms and/or soles. It is a continuous scale comprised of a horizontal or vertical line, 10 centimeters (cm) in length, anchored by word descriptors at each end (score ranges from “no pain” at 0 cm to “very severe pain” at 10 cm). The patient was asked to place a vertical ( | ) mark on the horizontal line to indicate the severity of the pain. Least square (LS) means, differences and confidence intervals were estimated by (Restricted maximum likelihood)−based MMRM including the fixed, categorical effects of treatment at each visit, region and the continuous effect of baseline at each visit as well as random effects of subject. Values post rescue medication or 6 weeks following last study treatment before discontinuation were censored. Unstructured covariance matrix was used. FAS

End point type

Secondary

End point timeframe

week 0 (baseline) and week 4.

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	38	20	21	20	41
Units: Score on a scale
least squares mean (confidence interval 95%)	-9.3 (-17.0 to -1.6)	-15.4 (-26.1 to -4.8)	-14.7 (-25.7 to -3.8)	-12.8 (-23.5 to -2.1)	-18.7 (-26.3 to -11.1)

Statistical analysis 10

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[15]

Method

Parameter type

Difference of adjusted means

Point estimate

-6.1

Confidence interval

level

95%

sides

2-sided

lower limit

-19.3

upper limit

7.1

Variability estimate

Standard error of the mean

Dispersion value

6.7

Notes
[15] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 11

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[16]

Method

Parameter type

Difference of adjusted means

Point estimate

-5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-18.8

upper limit

Variability estimate

Standard error of the mean

Dispersion value

6.8

Notes
[16] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 12

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[17]

Method

Parameter type

Difference of adjusted means

Point estimate

-3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-16.6

upper limit

9.7

Variability estimate

Standard error of the mean

Dispersion value

6.6

Notes
[17] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 13

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[18]

Method

Parameter type

Difference of adjusted means

Point estimate

-9.4

Confidence interval

level

95%

sides

2-sided

lower limit

-20.3

upper limit

1.4

Variability estimate

Standard error of the mean

Dispersion value

5.5

Notes
[18] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

Top of page

End point title

Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

End point description

Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16. The PPP Pain VAS is a unidimensional measure of pain intensity due to palmoplantar pustulosis on palms and/or soles. It is a continuous scale comprised of a horizontal or vertical line, 10 centimeters (cm) in length, anchored by word descriptors at each end (score ranges from “no pain” at 0 cm to “very severe pain” at 10 cm). The patient was asked to place a vertical ( | ) mark on the horizontal line to indicate the severity of the pain. Least square (LS) means, differences and confidence intervals were estimated by (Restricted maximum likelihood)−based MMRM including the fixed, categorical effects of treatment at each visit, region and the continuous effect of baseline at each visit as well as random effects of subject. Values post rescue medication or 6 weeks following last study treatment before discontinuation were censored. Unstructured covariance matrix was used. FAS

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16.

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	38	20	21	20	41
Units: Score on a scale
least squares mean (confidence interval 95%)	-14.7 (-22.7 to -6.7)	-18.7 (-29.8 to -7.7)	-13.8 (-24.8 to -2.8)	-18.9 (-30.0 to -7.8)	-22.4 (-30.2 to -14.6)

Statistical analysis 14

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[19]

P-value

= 0.5595

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-17.7

upper limit

9.6

Variability estimate

Standard error of the mean

Dispersion value

6.9

Notes
[19] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 15

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[20]

P-value

= 0.8968

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-12.7

upper limit

14.5

Variability estimate

Standard error of the mean

Dispersion value

6.9

Notes
[20] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 16

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[21]

P-value

= 0.5456

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-17.9

upper limit

9.5

Variability estimate

Standard error of the mean

Dispersion value

6.9

Notes
[21] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 17

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[22]

P-value

= 0.1762

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-7.7

Confidence interval

level

95%

sides

2-sided

lower limit

-19

upper limit

3.5

Variability estimate

Standard error of the mean

Dispersion value

5.7

Notes
[22] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 18

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[23]

P-value

= 0.1726 ^[24]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[23] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.
[24] - Adjusted for multiplicity.

Statistical analysis 19

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[25]

P-value

= 0.2353 ^[26]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[25] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 70% of the maximum effect was achieved at the “low dose” regimen.
[26] - Adjusted for multiplicity.

Statistical analysis 20

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[27]

P-value

= 0.1346 ^[28]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[27] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 25% of the maximum effect was achieved at the “medium-low dose” regimen.
[28] - Adjusted for multiplicity.

Statistical analysis 21

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[29]

P-value

= 0.195 ^[30]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[29] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 20% of maximum effect was achieved at the “low dose”, 95% of maximum effect was achieved at “medium high dose”.
[30] - Adjusted for multiplicity.

Statistical analysis 22

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[31]

P-value

= 0.1681 ^[32]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[31] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.
[32] - Adjusted for multiplicity.

Secondary: Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

Top of page

End point title

Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

End point description

PPP SI change from baseline at Week 16. The PPP SI is based on the severity score of individual components (erythema, pustules, and scaling/desquamation) of PPP ASI assessments. The most severely affected area based on pustules was identified by the investigator at baseline and assessed at all subsequent visits. The PPP SI was calculated by summing up the individual components of PPP ASI assessment (range 0 (best) to 12 (worst)) at each visit for the identified location. Least square (LS) means, differences and confidence intervals were estimated by (Restricted maximum likelihood)−based Mixed effect model for repeated measurements (MMRM) including the fixed, categorical effects of treatment at each visit, region and the continuous effect of baseline at each visit as well as random effects of subject. Values post rescue medication or 6 weeks following last study treatment before discontinuation were censored. Unstructured covariance matrix was used. Full Analysis Set was used.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16.

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	38	20	21	20	41
Units: Score on a scale
least squares mean (confidence interval 95%)	-2.7 (-3.4 to -2.0)	-3.3 (-4.3 to -2.4)	-3.2 (-4.2 to -2.3)	-3.5 (-4.4 to -2.5)	-2.8 (-3.4 to -2.1)

Statistical analysis 23

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[33]

P-value

= 0.2812

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.8

upper limit

0.5

Variability estimate

Standard error of the mean

Dispersion value

0.6

Notes
[33] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 24

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[34]

P-value

= 0.3357

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

0.6

Variability estimate

Standard error of the mean

Dispersion value

0.6

Notes
[34] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 25

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[35]

P-value

= 0.1809

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

0.4

Variability estimate

Standard error of the mean

Dispersion value

0.6

Notes
[35] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 26

Statistical analysis description

Kenward-Roger was used to estimate denominator degrees of freedom. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[36]

P-value

= 0.8322

Method

Mixed models analysis

Parameter type

Difference of adjusted means

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.9

Variability estimate

Standard error of the mean

Dispersion value

0.5

Notes
[36] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 27

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[37]

P-value

= 0.4035 ^[38]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[37] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.
[38] - Adjusted for multiplicity.

Statistical analysis 28

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[39]

P-value

= 0.2563 ^[40]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[39] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 70% of the maximum effect was achieved at the “low dose” regimen.
[40] - Adjusted for multiplicity.

Statistical analysis 29

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[41]

P-value

= 0.681 ^[42]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[41] - Mixed-effects Model Repeated Measures (MMRM) estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 25% of the maximum effect was achieved at the “medium-low dose” regimen.
[42] - Adjusted for multiplicity.

Statistical analysis 30

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[43]

P-value

= 0.4665 ^[44]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[43] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 20% of maximum effect was achieved at the “low dose”, 95% of maximum effect was achieved at “medium high dose”.
[44] - Adjusted for multiplicity.

Statistical analysis 31

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

140

Analysis specification

Pre-specified

Analysis type

^[45]

P-value

= 0.5565 ^[46]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[45] - MMRM estimates were used as input for the MCP-Mod. MMRM included‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured. Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.
[46] - Adjusted for multiplicity.

Secondary: Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

Top of page

End point title

Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

End point description

Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50). The PPP ASI is an investigator assessment of the extent and severity of palmoplantar pustulosis lesions on the palms and soles in PPP patients. This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 (best) to 72 (worst). It is a linear combination of the percent of surface area of skin that is affected on the palms and soles of the body and the severity of erythema, pustules, and scaling (desquamation). When (PPP ASI baseline - PPP ASI current)/ PPP ASI baseline * 100% >= 50%, PPP ASI50 = 1. Full Analysis Set (FAS): This patient set includes all patients who were randomised and received at least one dose of study drug. Only subjects with non missing endpoint data were included.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	43	22	21	22	44
Units: Participants	12	7	10	12	18

Statistical analysis 32

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[47]

Method

Parameter type

Risk difference (RD)

Point estimate

0.042

Confidence interval

level

95%

sides

2-sided

lower limit

-0.17

upper limit

0.281

Notes
[47] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 33

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[48]

Method

Parameter type

Risk difference (RD)

Point estimate

0.195

Confidence interval

level

95%

sides

2-sided

lower limit

-0.048

upper limit

0.432

Notes
[48] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 34

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[49]

Method

Parameter type

Risk difference (RD)

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

0.496

Notes
[49] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 35

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[50]

Method

Parameter type

Risk difference (RD)

Point estimate

0.129

Confidence interval

level

95%

sides

2-sided

lower limit

-0.067

upper limit

0.314

Notes
[50] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 36

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[51]

P-value

= 0.0613 ^[52]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[51] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[52] - Adjusted for multiplicity.

Statistical analysis 38

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[53]

P-value

= 0.1449 ^[54]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[53] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[54] - Adjusted for multiplicity.

Statistical analysis 37

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[55]

P-value

= 0.0628 ^[56]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[55] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[56] - Adjusted for multiplicity.

Statistical analysis 39

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the MCP-Mod approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05). Assumed 20% of maximum effect was achieved at the “low dose”, 95% of maximum effect was achieved at “medium high dose”.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[57]

P-value

= 0.046 ^[58]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[57] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[58] - Adjusted for multiplicity.

Statistical analysis 40

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the MCP-Mod approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05). Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[59]

P-value

= 0.0677 ^[60]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[59] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[60] - Adjusted for multiplicity.

Secondary: Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

Top of page

End point title

Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

End point description

Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75). The PPP ASI is an investigator assessment of the extent and severity of palmoplantar pustulosis lesions on the palms and soles in PPP patients. This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 (best) to 72 (worst). It is a linear combination of the percent of surface area of skin that is affected on the palms and soles of the body and the severity of erythema, pustules, and scaling (desquamation). When (PPP ASI baseline - PPP ASI current)/ PPP ASI baseline * 100% >= 75%, PPP ASI75 = 1. Full Analysis Set (FAS): This patient set includes all patients who were randomised and received at least one dose of study drug. Only subjects with non missing endpoint data were included.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	43	22	21	22	44
Units: Participants	3	3	6	4	9

Statistical analysis 41

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[61]

Method

Parameter type

Risk difference (RD)

Point estimate

0.063

Confidence interval

level

95%

sides

2-sided

lower limit

-0.069

upper limit

0.256

Notes
[61] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 42

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[62]

Method

Parameter type

Risk difference (RD)

Point estimate

0.188

Confidence interval

level

95%

sides

2-sided

lower limit

0.018

upper limit

0.405

Notes
[62] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 43

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[63]

Method

Parameter type

Risk difference (RD)

Point estimate

0.102

Confidence interval

level

95%

sides

2-sided

lower limit

-0.042

upper limit

0.303

Notes
[63] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 44

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[64]

Method

Parameter type

Risk difference (RD)

Point estimate

0.113

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.25

Notes
[64] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 45

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[65]

P-value

= 0.0536 ^[66]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[65] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[66] - Adjusted for multiplicity.

Statistical analysis 46

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[67]

P-value

= 0.0476 ^[68]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[67] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[68] - Adjusted for multiplicity.

Statistical analysis 47

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[69]

P-value

= 0.1076 ^[70]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[69] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[70] - Adjusted for multiplicity.

Statistical analysis 48

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[71]

P-value

= 0.0606 ^[72]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[71] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[72] - Adjusted for multiplicity.

Statistical analysis 49

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the MCP-Mod approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05). Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[73]

P-value

= 0.0824 ^[74]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[73] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[74] - Adjusted for multiplicity.

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

Top of page

End point title

Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

End point description

Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16. The PPP PGA relies on investigator assessment of the patient’s skin presentation on the palms and soles. The investigator scored the individual components (erythema, pustules, and scaling/crusting) from 0 (best) to 4 (worst) as clear, almost clear, mild, moderate or severe. PPP PGA categorization is based on the mean of the four individual components. Full Analysis Set (FAS): This patient set includes all patients who were randomised and received at least one dose of study drug. Only subjects with non missing endpoint data were included.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	43	22	21	22	44
Units: Participants	2	6	4	4	9

Statistical analysis 50

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[75]

Method

Parameter type

Risk difference (RD)

Point estimate

0.211

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

0.422

Notes
[75] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 52

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[76]

Method

Parameter type

Risk difference (RD)

Point estimate

0.125

Confidence interval

level

95%

sides

2-sided

lower limit

-0.022

upper limit

0.328

Notes
[76] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 53

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[77]

Method

Parameter type

Risk difference (RD)

Point estimate

0.144

Confidence interval

level

95%

sides

2-sided

lower limit

0.009

upper limit

0.282

Notes
[77] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 51

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[78]

Method

Parameter type

Risk difference (RD)

Point estimate

0.13

Confidence interval

level

95%

sides

2-sided

lower limit

-0.018

upper limit

0.339

Notes
[78] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 54

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[79]

P-value

= 0.0333 ^[80]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[79] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[80] - Adjusted for multiplicity.

Statistical analysis 55

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[81]

P-value

= 0.0221 ^[82]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[81] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[82] - Adjusted for multiplicity.

Statistical analysis 56

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[83]

P-value

= 0.0707 ^[84]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[83] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[84] - Adjusted for multiplicity.

Statistical analysis 57

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[85]

P-value

= 0.0578 ^[86]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[85] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[86] - Adjusted for multiplicity.

Statistical analysis 58

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the MCP-Mod approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05). Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[87]

P-value

= 0.0771 ^[88]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[87] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[88] - Adjusted for multiplicity.

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

Top of page

End point title

Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

End point description

Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16. The PPP PGA relies on investigator assessment of the patient’s skin presentation on the palms and soles. The investigator scored the pustules from 0 (best) to 4 (worst) as clear, almost clear, mild, moderate or severe. Full Analysis Set (FAS): This patient set includes all patients who were randomised and received at least one dose of study drug. Only subjects with non missing endpoint data were included.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 16

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	43	22	21	22	44
Units: Participants	5	7	6	8	14

Statistical analysis 59

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[89]

Method

Parameter type

Risk difference (RD)

Point estimate

0.202

Confidence interval

level

95%

sides

2-sided

lower limit

-0.005

upper limit

0.427

Notes
[89] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 60

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[90]

Method

Parameter type

Risk difference (RD)

Point estimate

0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.032

upper limit

0.401

Notes
[90] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 61

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[91]

Method

Parameter type

Risk difference (RD)

Point estimate

0.248

Confidence interval

level

95%

sides

2-sided

lower limit

0.032

upper limit

0.471

Notes
[91] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 62

Statistical analysis description

Confidence intervals were calculated using the cumulative distribution function method of Reeve. Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[92]

Method

Parameter type

Risk difference (RD)

Point estimate

0.202

Confidence interval

level

95%

sides

2-sided

lower limit

0.024

upper limit

0.367

Notes
[92] - Logistic regression with fixed classification effects included treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.

Statistical analysis 63

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[93]

P-value

= 0.0158 ^[94]

Method

MCP-Mod linear model fit

Confidence interval

Notes
[93] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[94] - Adjusted for multiplicity.

Statistical analysis 64

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[95]

P-value

= 0.012 ^[96]

Method

MCP-Mod Emax model fit

Confidence interval

Notes
[95] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[96] - Adjusted for multiplicity.

Statistical analysis 65

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[97]

P-value

= 0.0429 ^[98]

Method

MCP-Mod Exponential model fit

Confidence interval

Notes
[97] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[98] - Adjusted for multiplicity.

Statistical analysis 66

Statistical analysis description

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[99]

P-value

= 0.0229 ^[100]

Method

MCP-Mod Logistic model fit

Confidence interval

Notes
[99] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[100] - Adjusted for multiplicity.

Statistical analysis 67

Statistical analysis description

A flat vs. non-flat dose-response relationship across the 4 doses of Spesolimab and placebo was tested using the MCP-Mod approach which evaluated simultaneously 5 different plausible dose-response patterns (linear, Emax, exponential, logistic, Sigmoid Emax) while protecting the overall probability of type I error (one-sided alpha of 0.05). Assumed 10% of the maximum effect was achieved at “low dose”, 80% of the maximum effect was achieved at the “medium-high dose”.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’ v Spesolimab ‘Speso Medium-low’ v Spesolimab ‘Speso Medium-high’ v Spesolimab ‘Speso High’

Number of subjects included in analysis

152

Analysis specification

Pre-specified

Analysis type

^[101]

P-value

= 0.03 ^[102]

Method

MCP-Mod Sigmoid Emax model fit

Confidence interval

Notes
[101] - Logistic regression estimates were used as input for the MCP-Mod, with fixed classification effects including treatment and region (Japan vs. Non-Japan). In case 0 event are observed a penalized regression based on the Firth’s bias reduction method was used. The estimates from the logistic regression are on the logit scale, the difference in proportions were calculated as the difference between the predicted probabilities in the treatment groups on the original scale.
[102] - Adjusted for multiplicity.

Secondary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

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End point title

The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

End point description

The percentage change in PPP ASI at Week 52 from baseline. The PPP ASI is an investigator assessment of the extent and severity of palmoplantar pustulosis lesions on the palms and soles in PPP patients. This tool provides a numeric scoring for patients overall PPP disease state, ranging from 0 (best) to 72 (worst). It is a linear combination of the percent of surface area of skin that is affected on the palms and soles of the body and the severity of erythema, pustules, and scaling (desquamation). LS means, differences and confidence intervals were estimated by (Restricted maximum likelihood)−based MMRM including the fixed, categorical effects of treatment at each visit, region and the continuous effect of baseline at each visit as well as random effects of subject. Values post rescue medication or 6 weeks following last study treatment before discontinuation were censored. Unstructured covariance matrix was used. Full Analysis Set.

End point type

Secondary

End point timeframe

week 0 (baseline) and week 52

End point values	Placebo & Spesolimab	Spesolimab ‘Speso Low’	Spesolimab ‘Speso Medium-low’	Spesolimab ‘Speso Medium-high’	Spesolimab ‘Speso High’
Number of subjects analysed	32	19	18	17	32
Units: Percentage of change in PPP ASI
least squares mean (confidence interval 95%)	-54.6 (-65.8 to -43.3)	-73.3 (-87.9 to -58.6)	-73.8 (-89.1 to -58.6)	-81.2 (-96.4 to -66.1)	-60.0 (-70.9 to -49.2)

Statistical analysis 68

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[103]

Method

Parameter type

Difference of adjusted means

Point estimate

-18.7

Confidence interval

level

95%

sides

2-sided

lower limit

-37.2

upper limit

-0.2

Variability estimate

Standard error of the mean

Dispersion value

9.3

Notes
[103] - MMRM included ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 69

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-low’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[104]

Method

Parameter type

Difference of adjusted means

Point estimate

-19.3

Confidence interval

level

95%

sides

2-sided

lower limit

-38.3

upper limit

-0.2

Variability estimate

Standard error of the mean

Dispersion value

9.6

Notes
[104] - MMRM included ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 70

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso Medium-high’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[105]

Method

Parameter type

Difference of adjusted means

Point estimate

-26.6

Confidence interval

level

95%

sides

2-sided

lower limit

-45.5

upper limit

-7.8

Variability estimate

Standard error of the mean

Dispersion value

9.5

Notes
[105] - MMRM included ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Statistical analysis 71

Statistical analysis description

Difference was calculated as Speso - placebo.

Comparison groups

Placebo & Spesolimab v Spesolimab ‘Speso High’

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

^[106]

Method

Parameter type

Difference of adjusted means

Point estimate

-5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-21.1

upper limit

10.2

Variability estimate

Standard error of the mean

Dispersion value

7.9

Notes
[106] - MMRM included ‘baseline’ as a continuous covariate, and ‘visit’, ‘treatment’, ‘region’ (stratification according to Japan vs. non-Japan), ‘visit*treatment’ and ‘visit*baseline’ interaction as fixed effects as well as the random ‘subject’ effect. Covariance structure= Unstructured.

Adverse events

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Timeframe for reporting adverse events

From the first until the last day of study drug administration + 112 days, up to 68 weeks.

Adverse event reporting additional description

Safety analysis set (SAF): This patient set includes all patients who were randomised and received at least one dose of study drug.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

24.0

Reporting group title

Placebo

Reporting group description

Subcutaneous injections of placebo matching Spesolimab from week 0 to 16.

Reporting group title

Speso High

Reporting group description

Subcutaneous injections of Spesolimab in a high dose scheme for a total treatment time of 52 weeks.

Reporting group title

Speso Medium-low

Reporting group description

Subcutaneous injections of Spesolimab in a medium-low dose scheme for a total treatment time of 52 weeks.

Reporting group title

Speso Medium-high

Reporting group description

Subcutaneous injections of Spesolimab in a medium-high dose scheme for a total treatment time of 52 weeks.

Reporting group title

Speso Post Placebo

Reporting group description

Subcutaneous injections of Spesolimab starting at week 16, for a total treatment time until week 52.

Reporting group title

Speso Low

Reporting group description

Subcutaneous injections of Spesolimab in a low dose scheme for a total treatment time of 52 weeks.

Serious adverse events	Placebo	Speso High	Speso Medium-low	Speso Medium-high	Speso Post Placebo	Speso Low
Total subjects affected by serious adverse events
subjects affected / exposed	2 / 43 (4.65%)	3 / 44 (6.82%)	5 / 21 (23.81%)	3 / 22 (13.64%)	3 / 38 (7.89%)	3 / 22 (13.64%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 21 (4.76%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Pneumothorax traumatic
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	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
Rib fracture
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 21 (4.76%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	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
Spinal compression fracture
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	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
Congenital, familial and genetic disorders
Atrial septal defect
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Circulatory collapse
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 21 (4.76%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebral infarction
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal artery embolism
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences causally related to treatment / all	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
Gastrointestinal disorders
Constipation
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dyshidrotic eczema
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Henoch-Schonlein purpura
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palmoplantar pustulosis
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pustular psoriasis
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar disorder
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Depression
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 21 (4.76%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Foot deformity
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	1 / 21 (4.76%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhabdomyolysis
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	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	Speso High	Speso Medium-low	Speso Medium-high	Speso Post Placebo	Speso Low
Total subjects affected by non serious adverse events
subjects affected / exposed	24 / 43 (55.81%)	31 / 44 (70.45%)	17 / 21 (80.95%)	17 / 22 (77.27%)	22 / 38 (57.89%)	17 / 22 (77.27%)
Injury, poisoning and procedural complications
Arthropod bite
subjects affected / exposed	0 / 43 (0.00%)	3 / 44 (6.82%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences all number	0	5	0	0	1	0
Contusion
subjects affected / exposed	0 / 43 (0.00%)	4 / 44 (9.09%)	0 / 21 (0.00%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences all number	0	4	0	0	1	0
Skin abrasion
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Cardiac disorders
Palpitations
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	2 / 22 (9.09%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences all number	1	0	0	2	0	0
Nervous system disorders
Headache
subjects affected / exposed	1 / 43 (2.33%)	5 / 44 (11.36%)	0 / 21 (0.00%)	2 / 22 (9.09%)	3 / 38 (7.89%)	2 / 22 (9.09%)
occurrences all number	1	13	0	5	3	2
General disorders and administration site conditions
Injection site erythema
subjects affected / exposed	0 / 43 (0.00%)	3 / 44 (6.82%)	1 / 21 (4.76%)	4 / 22 (18.18%)	2 / 38 (5.26%)	3 / 22 (13.64%)
occurrences all number	0	6	2	10	4	5
Injection site pain
subjects affected / exposed	3 / 43 (6.98%)	1 / 44 (2.27%)	3 / 21 (14.29%)	1 / 22 (4.55%)	2 / 38 (5.26%)	0 / 22 (0.00%)
occurrences all number	10	1	18	1	12	0
Injection site reaction
subjects affected / exposed	0 / 43 (0.00%)	20 / 44 (45.45%)	5 / 21 (23.81%)	5 / 22 (22.73%)	4 / 38 (10.53%)	3 / 22 (13.64%)
occurrences all number	0	105	20	15	11	23
Pyrexia
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	2 / 21 (9.52%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	2	0	0	2
Gastrointestinal disorders
Abdominal pain upper
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	2 / 22 (9.09%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences all number	0	0	0	2	1	0
Constipation
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	2 / 38 (5.26%)	0 / 22 (0.00%)
occurrences all number	1	0	0	0	2	0
Dental caries
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	2 / 38 (5.26%)	0 / 22 (0.00%)
occurrences all number	0	0	0	1	2	0
Diarrhoea
subjects affected / exposed	1 / 43 (2.33%)	1 / 44 (2.27%)	2 / 21 (9.52%)	2 / 22 (9.09%)	1 / 38 (2.63%)	3 / 22 (13.64%)
occurrences all number	1	1	2	4	1	4
Skin and subcutaneous tissue disorders
Acne
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	3 / 21 (14.29%)	1 / 22 (4.55%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	4	1	0	1
Dermatitis contact
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	2 / 38 (5.26%)	1 / 22 (4.55%)
occurrences all number	1	0	0	0	2	1
Eczema
subjects affected / exposed	2 / 43 (4.65%)	0 / 44 (0.00%)	2 / 21 (9.52%)	1 / 22 (4.55%)	2 / 38 (5.26%)	6 / 22 (27.27%)
occurrences all number	2	0	2	1	2	12
Palmoplantar pustulosis
subjects affected / exposed	4 / 43 (9.30%)	5 / 44 (11.36%)	1 / 21 (4.76%)	1 / 22 (4.55%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	5	5	1	1	0	1
Pruritus
subjects affected / exposed	1 / 43 (2.33%)	2 / 44 (4.55%)	0 / 21 (0.00%)	1 / 22 (4.55%)	1 / 38 (2.63%)	2 / 22 (9.09%)
occurrences all number	1	2	0	1	1	2
Rash
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	1	0	3
Urticaria
subjects affected / exposed	0 / 43 (0.00%)	3 / 44 (6.82%)	1 / 21 (4.76%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences all number	0	3	1	0	1	0
Psychiatric disorders
Insomnia
subjects affected / exposed	3 / 43 (6.98%)	1 / 44 (2.27%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	3	1	0	1	0	2
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	6 / 43 (13.95%)	3 / 44 (6.82%)	0 / 21 (0.00%)	2 / 22 (9.09%)	4 / 38 (10.53%)	3 / 22 (13.64%)
occurrences all number	6	3	0	2	5	3
Back pain
subjects affected / exposed	0 / 43 (0.00%)	2 / 44 (4.55%)	1 / 21 (4.76%)	2 / 22 (9.09%)	0 / 38 (0.00%)	4 / 22 (18.18%)
occurrences all number	0	2	1	3	0	4
Musculoskeletal chest pain
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	2 / 22 (9.09%)
occurrences all number	0	0	0	0	0	2
Musculoskeletal stiffness
subjects affected / exposed	1 / 43 (2.33%)	1 / 44 (2.27%)	2 / 21 (9.52%)	0 / 22 (0.00%)	1 / 38 (2.63%)	0 / 22 (0.00%)
occurrences all number	1	1	2	0	1	0
Osteoarthritis
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	2 / 38 (5.26%)	1 / 22 (4.55%)
occurrences all number	0	1	0	0	2	1
Pain in extremity
subjects affected / exposed	1 / 43 (2.33%)	0 / 44 (0.00%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	2 / 22 (9.09%)
occurrences all number	1	0	0	0	0	2
Pustulotic arthro-osteitis
subjects affected / exposed	1 / 43 (2.33%)	2 / 44 (4.55%)	0 / 21 (0.00%)	2 / 22 (9.09%)	2 / 38 (5.26%)	0 / 22 (0.00%)
occurrences all number	1	2	0	2	2	0
Infections and infestations
Nasopharyngitis
subjects affected / exposed	5 / 43 (11.63%)	4 / 44 (9.09%)	2 / 21 (9.52%)	2 / 22 (9.09%)	3 / 38 (7.89%)	3 / 22 (13.64%)
occurrences all number	6	5	2	2	4	4
Rhinitis
subjects affected / exposed	3 / 43 (6.98%)	1 / 44 (2.27%)	0 / 21 (0.00%)	0 / 22 (0.00%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	5	1	0	0	0	1
Sinusitis
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	2 / 22 (9.09%)	0 / 38 (0.00%)	0 / 22 (0.00%)
occurrences all number	0	1	0	3	0	0
Upper respiratory tract infection
subjects affected / exposed	0 / 43 (0.00%)	0 / 44 (0.00%)	2 / 21 (9.52%)	1 / 22 (4.55%)	0 / 38 (0.00%)	1 / 22 (4.55%)
occurrences all number	0	0	2	3	0	2
Urinary tract infection
subjects affected / exposed	0 / 43 (0.00%)	1 / 44 (2.27%)	0 / 21 (0.00%)	1 / 22 (4.55%)	0 / 38 (0.00%)	3 / 22 (13.64%)
occurrences all number	0	1	0	1	0	3

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Were there any global substantial amendments to the protocol? No

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:
Multi-center, double-blind, randomised, placebo-controlled, phase IIb dose-finding study to evaluate efficacy and safety of different subcutaneous doses of BI 655130 in patients with moderate to severe Palmoplantar Pustulosis (PPP)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

Primary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

Secondary: Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

Secondary: Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

Secondary: Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

Secondary: Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

Secondary: Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

Secondary: Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

Secondary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

Secondary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

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Outside EU/EEA

Clinical trials

Clinical Trial Results: Multi-center, double-blind, randomised, placebo-controlled, phase IIb dose-finding study to evaluate efficacy and safety of different subcutaneous doses of BI 655130 in patients with moderate to severe Palmoplantar Pustulosis (PPP)

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

Primary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 16 from baseline

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 4

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

Secondary: Change from baseline in Palmoplantar Pustulosis Pain Visual Analogue Scale (VAS) score at Week 16

Secondary: Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

Secondary: Palmoplantar Pustulosis Severity Index (PPP SI) change from baseline at Week 16

Secondary: Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

Secondary: Number of patients achieving a 50% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI50)

Secondary: Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

Secondary: Number of patients achieving a 75% decrease from baseline in Palmoplantar Pustulosis Area and Severity Index score at week 16 (PPP ASI75)

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

Secondary: Number of patients with Palmoplantar Pustulosis Physician Global Assessment (PPP PGA) pustules clear/almost clear (0 or 1) at Week 16

Secondary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

Secondary: The percentage change in Palmoplantar Pustulosis Area and Severity Index (PPP ASI) at Week 52 from baseline

Adverse events

Adverse events

More information

Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
Multi-center, double-blind, randomised, placebo-controlled, phase IIb dose-finding study to evaluate efficacy and safety of different subcutaneous doses of BI 655130 in patients with moderate to severe Palmoplantar Pustulosis (PPP)