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Clinical Trial Results:
Phase 3, Multicenter, Randomized, Double-Blind, Parallel Group, Placebo-Controlled Study to Evaluate the Efficacy and Safety of Certolizumab Pegol in Subjects With Adult-Onset Active and Progressive Psoriatic Arthritis (PsA)

Summary
EudraCT number	2009-011720-59
Trial protocol	FR DE ES GB BE HU NL CZ IE IT
Global end of trial date	24 Aug 2015

Results information
Results version number	v1(current)
This version publication date	08 Sep 2016
First version publication date	08 Sep 2016
Other versions

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

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Trial information

Top of page

Sponsor protocol code

PsA001

ISRCTN number

-

US NCT number

NCT01087788

WHO universal trial number (UTN)

-

Sponsor organisation name

UCB BIOSCIENCES GmbH

Sponsor organisation address

Alfred-Nobel-Strasse 10, Monheim, Germany, 40789

Public contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Scientific contact

Clin Trial Reg & Results Disclosure, UCB BIOSCIENCES GmbH, clinicaltrials@ucb.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

13 Apr 2016

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

24 Aug 2015

Was the trial ended prematurely?

No

Main objective of the trial

To demonstrate the efficacy of Certolizumab pegol (CZP) administered sc at the dose of 200mg every two weeks (Q2W) or 400mg every four weeks (Q4W) after loading with 400mg at Weeks 0, 2, and 4 on the signs and symptoms of active psoriatic arthritis (PsA) and on the inhibition of progression of structural damage in adults with active PsA

Protection of trial subjects

Not applicable

Background therapy

Not applicable

Evidence for comparator

Not applicable

Actual start date of recruitment

02 Mar 2010

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

No

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 14

Country: Number of subjects enrolled

United States: 84

Country: Number of subjects enrolled

Argentina: 50

Country: Number of subjects enrolled

Brazil: 6

Country: Number of subjects enrolled

Mexico: 4

Country: Number of subjects enrolled

Belgium: 1

Country: Number of subjects enrolled

Germany: 33

Country: Number of subjects enrolled

Ireland: 1

Country: Number of subjects enrolled

Italy: 8

Country: Number of subjects enrolled

Spain: 6

Country: Number of subjects enrolled

United Kingdom: 6

Country: Number of subjects enrolled

Czech Republic: 67

Country: Number of subjects enrolled

Hungary: 28

Country: Number of subjects enrolled

Poland: 101

Worldwide total number of subjects

409

EEA total number of subjects

251

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

383

From 65 to 84 years

26

85 years and over

0

Subject disposition

Top of page

Recruitment details

This study started to enroll patients in March 2010 and concluded in August 2015.

Screening details

The study included a 24-week Double-Blind, a 24-week Dose-Blind, and an Open-Label Treatment Period. 409 subjects are included in Randomized Set (RS) shown in the Participant Flow, which is an Intention- to- Treat (ITT) dataset.

Period 1 title

24-weeks Double-blind Period

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Subject, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections every 2 Weeks or every 4 Weeks

CZP 200 mg Q2W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

CZP 400 mg Q4W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

Number of subjects in period 1	Placebo	CZP 200 mg Q2W	CZP 400 mg Q4W
Started	136	138	135
Completed	120	128	120
Not completed	16	10	15
AE, serious fatal	-	1	1
Consent withdrawn by subject	7	2	5
AE, unknown type	-	-	1
AE, non-serious non-fatal	2	1	2
Other reason	1	2	1
AE, serious non-fatal	-	2	3
Lost to follow-up	4	1	1
Lack of efficacy	2	-	1
Protocol deviation	-	1	-

Period 2 title

24-weeks Double-blind Period

Is this the baseline period?

No

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Assessor, Carer, Investigator, Subject

Are arms mutually exclusive

Yes

Placebo

Arm description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections every 2 Weeks or every 4 Weeks

CZP 200 mg Q2W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

CZP 400 mg Q4W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

Number of subjects in period 2	Placebo	CZP 200 mg Q2W	CZP 400 mg Q4W
Started	120	128	120
Completed	113	123	114
Not completed	7	5	6
AE, serious fatal	-	1	-
Consent withdrawn by subject	1	-	-
AE, non-serious non-fatal	2	1	1
other	1	-	1
AE, serious non-fatal	2	1	2
Lost to follow-up	1	-	1
Lack of efficacy	-	2	1

Period 3 title

Open-Label Period

Is this the baseline period?

No

Allocation method

Not applicable

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Placebo

Arm description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection/infusion in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections every 2 Weeks or every 4 Weeks

CZP 200 mg Q2W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

CZP 400 mg Q4W

Arm description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Arm type

Experimental

Investigational medicinal product name

Certolizumab pegol

Investigational medicinal product code

Certolizumab pegol

Other name

Cimzia

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Subcutaneous injections: 200 mg every 2 Weeks or 400 mg every 4 Weeks

Number of subjects in period 3 ^[1]	Placebo	CZP 200 mg Q2W	CZP 400 mg Q4W
Started	111	121	114
Completed	81	97	86
Not completed	30	24	28
AE, serious fatal	2	-	1
Consent withdrawn by subject	13	8	10
AE, non-serious unknown	1	-	-
AE, non-serious non-fatal	6	4	4
SAE, non-fatal+AE, non-serious non-fatal	-	1	-
other	1	1	4
AE, serious non-fatal	1	3	4
Lost to follow-up	-	4	2
Lack of efficacy	4	2	3
Protocol deviation	2	1	-

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: 4 subjects completed the Dose-Blind Period and then withdrew from the study rather than entering the Open-Label Period.

Baseline characteristics

Top of page

Reporting group title

Placebo

Reporting group description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Reporting group title

CZP 200 mg Q2W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Reporting group title

CZP 400 mg Q4W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Reporting group values	Placebo	CZP 200 mg Q2W	CZP 400 mg Q4W	Total
Number of subjects	136	138	135	409
Age Categorical
Units: Subjects
<=18 years	0	0	0	0
Between 18 and 65 years	129	126	128	383
>=65 years	7	12	7	26
Age Continuous
Units: years
arithmetic mean (standard deviation)	47.3 ± 11.1	48.2 ± 12.3	47.1 ± 10.8	-
Gender Categorical
Units: Subjects
Female	79	74	73	226
Male	57	64	62	183

End points

Top of page

Reporting group title

Placebo

Reporting group description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Reporting group title

CZP 200 mg Q2W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Reporting group title

CZP 400 mg Q4W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Reporting group title

Placebo

Reporting group description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Reporting group title

CZP 200 mg Q2W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Reporting group title

CZP 400 mg Q4W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Reporting group title

Placebo

Reporting group description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Reporting group title

CZP 200 mg Q2W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Reporting group title

CZP 400 mg Q4W

Reporting group description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Subject analysis set title

All CZP 200 mg Q2W

Subject analysis set type

Safety analysis

Subject analysis set description

This arm includes all subjects who were randomized to CZP 200 mg Q2W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 200 mg Q2W. Subjects received one injection of 200 mg CZP and one injection of Placebo every two weeks to maintain the study blind.

Subject analysis set title

All CZP 400 mg Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

This arm includes all subjects who were randomized to CZP 400 mg Q4W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 400 mg Q4W. Subjects received two injections of Placebo every four weeks in between the two injections of 200 mg CZP to maintain the study blind.

Subject analysis set title

All CZP 200 mg + 400 mg

Subject analysis set type

Safety analysis

Subject analysis set description

This arm shows all patients treated with Certolizumab Pegol (CZP) at least once. Hence, this arm is a combination of arm All CZP 200 mg Q2W and arm All CZP 400 mg Q4W.

Subject analysis set title

Placebo (Randomized Set)

Subject analysis set type

Full analysis

Subject analysis set description

Matching Placebo to Certolizumab Pegol (CZP) injections from Week 0 to Week 24. Placebo subjects who did not achieve certain predefined response criteria at both Weeks 14 and 16 left the Placebo group and were re-randomized to either CZP 200 mg Q2W or CZP 400 mg Q4W arm on Week 16. After 24 weeks, all subjects were re-randomized to active treatment with CZP 200 mg every two weeks (Q2W) or CZP 400 mg every four weeks (Q4W).

Subject analysis set title

CZP 200 mg Q2W (Randomized Set)

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W) from Week 6 onwards. At every visit, subjects received one injection of 200 mg CZP and one injection of Placebo to maintain the study blind.

Subject analysis set title

CZP 400 mg Q4W (Randomized Set)

Subject analysis set type

Full analysis

Subject analysis set description

Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 400 mg CZP sc every 4 weeks (Q4W) from Week 8 onwards. Subjects received 2 injections of Placebo every 4 weeks in between the 2 injections of 200 mg CZP to maintain the study blind.

Subject analysis set title

CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Subject analysis set type

Full analysis

Subject analysis set description

This combined group includes subjects of the two treatment arms CZP 200 mg Q2W and CZP 400 mg Q4W used in some analyses. Subjects received Certolizumab Pegol (CZP) 400 mg subcutaneous (sc) on Weeks 0, 2 and 4, followed by 200 mg CZP sc every 2 weeks (Q2W)/ 400 mg CZP sc every 4 weeks (Q4W) from Week 6/ Week 8 onwards. Subjects in both CZP arms received additional placebo injections to maintain the study blind.

Primary: American College of Rheumatology 20 (ACR20) response at Week 12

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End point title

American College of Rheumatology 20 (ACR20) response at Week 12

End point description

ACR20 responders are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS).

End point type

Primary

End point timeframe

Week 12

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	136	138	135
Units: percentage of participants
number (confidence interval 95%)
Percentage of participants	24.3 (17.1 to 31.5)	58 (49.7 to 66.2)	51.9 (43.4 to 60.3)

Statistical Analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[1]

Method

Wald-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

33.7

Confidence interval

level

95%

sides

2-sided

lower limit

22.8

upper limit

44.6

Notes
[1] - Difference of Certolizumab Pegol 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

Statistical Analysis 2

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[2]

Method

Wald-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

27.6

Confidence interval

level

95%

sides

2-sided

lower limit

16.5

upper limit

38.7

Notes
[2] - Difference of Certolizumab Pegol 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

Primary: Change from Baseline in modified Total Sharp Score (mTSS) in modification for Psoriatic Arthritis at Week 24

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End point title

Change from Baseline in modified Total Sharp Score (mTSS) in modification for Psoriatic Arthritis at Week 24

End point description

Van der Heijde modified Total Sharp Score (mTSS) is a methodology to assess the degree of joint damage by quantifying the extent of bone erosions and joint space narrowing for 64 and 52 joints, respectively, with higher scores representing greater damage. mTSS (bone erosions) ranges from 0 (best possible outcome) to 320 (worst possible outcome); mTSS (joint space narrowing) ranges from 0 (best possible outcome) to 208 (worst possible outcome); and total score ranges from 0 (best possible outcome) to 528 (worst possible outcome). For the pre-defined analysis of this outcome measure, 0 was used for Baseline and the maximum observed mTSS value was used for Week 24 for those subjects which had less than 2 radiographs. The re-analysis is restricted to those subjects in the Randomized Set who have at least 2 x-ray values at scheduled visits, which are at least 8 weeks apart.

End point type

Primary

End point timeframe

From Baseline to Week 24

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)	CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	136	138	135	273
Units: units on a scale
least squares mean (confidence interval 95%)
Pre-defined results	28.92 (13.73 to 44.11)	11.52 (-3.4 to 26.45)	25.05 (9.48 to 40.61)	18.28 (6.34 to 30.23)
Re-analysis results ( n = 123, 130, 123, 253)	0.18 (0.04 to 0.33)	-0.02 (-0.16 to 0.11)	0.09 (-0.05 to 0.23)	0.03 (-0.08 to 0.14)

Statistical Analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the pre-defined primary analysis.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

409

Analysis specification

Pre-specified

Analysis type

P-value

= 0.203 ^[3]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-10.64

Confidence interval

level

95%

sides

2-sided

lower limit

-27.05

upper limit

5.77

Variability estimate

Standard error of the mean

Dispersion value

8.35

Notes
[3] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

Statistical Analysis 2

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

P-value

= 0.017 ^[4]

Method

ANCOVA

Parameter type

Median difference (net)

Point estimate

-0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

-0.04

Variability estimate

Standard error of the mean

Dispersion value

0.09

Notes
[4] - Difference of CZP 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

Secondary: American College of Rheumatology 20 (ACR20) response at Week 24

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End point title

American College of Rheumatology 20 (ACR20) response at Week 24

End point description

ACR20 responders are those subjects with at least 20 % improvement from Baseline for Tender Joint Count (TJC), Swollen Joint Count (SJC), and at least 3 of the 5 remaining core set measures: 1) Health Assessment Questionnaire-Disability Index (HAQ-DI), 2) C-reactive Protein (CRP), 3) Patient's Assessment of Arthritis Pain-Visual Analog Scale (PAAP-VAS), 4) Patient's Global Assessment of Disease Activity-Visual Analog Scale (PtGADA-VAS), 5) Physician's Global Assessment of Disease Activity-Visual Analog Scale (PhGADA-VAS).

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	136	138	135
Units: percentage of participants
number (confidence interval 95%)
percentage of participants	23.5 (16.4 to 30.7)	63.8 (55.7 to 71.8)	56.3 (47.9 to 64.7)

Statistical Analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W (Randomized Set)

Number of subjects included in analysis

274

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[5]

Method

Wald-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

40.2

Confidence interval

level

95%

sides

2-sided

lower limit

29.5

upper limit

51

Notes
[5] - Difference of Certolizumab Pegol 200 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

Statistical Analysis 2

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

271

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[6]

Method

Wald-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

32.8

Confidence interval

level

95%

sides

2-sided

lower limit

21.8

upper limit

43.8

Notes
[6] - Difference of Certolizumab Pegol 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

Secondary: Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 24

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End point title

Change from Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 24

End point description

The HAQ-DI is a measure of function in Arthritis. There are 20 items in eight categories that represent a comprehensive set of functional activities on a scale from 0 (without difficulty) to 3 (unable to perform without assistance). The category scores are averaged into an overall HAQ-DI from 0 to 3. Scores of 0 to 1 generally represent mild to moderate difficulty, 1 to 2 represent moderate to severe disability, and 2 to 3 indicate severe to very severe disability. A negative value in HAQ-DI change from Baseline indicates an improvement from Baseline. The higher the negative value, the higher the improvement.

End point type

Secondary

End point timeframe

From Baseline to Week 24

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)	CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	136	138	135	273
Units: units on a scale
least squares mean (confidence interval 95%)
units on a scale	-0.19 (-0.29 to -0.09)	-0.54 (-0.64 to -0.44)	-0.46 (-0.56 to -0.36)	-0.5 (-0.58 to -0.42)

Statistical Analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

409

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[7]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.31

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

-0.2

Variability estimate

Standard error of the mean

Dispersion value

0.06

Notes
[7] - Difference of CZP 200 mg + 400 mg vs. Placebo (and corresponding 95 % Confidence Interval and pvalue) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline HAQ-DI score as a covariate.

Secondary: Psoriasis Area Severity Index (PASI75) response at Week 24 in the subgroup of subjects with Psoriasis (PSO) involving at least 3 % Body Surface Area (BSA) at Baseline

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End point title

Psoriasis Area Severity Index (PASI75) response at Week 24 in the subgroup of subjects with Psoriasis (PSO) involving at least 3 % Body Surface Area (BSA) at Baseline

End point description

The PASI75 response assessments are based on at least 75 % improvement in the PASI score from Baseline. The PASI score is a measure of the average redness, thickness, and scaliness of the psoriatic skin lesions (each graded on a 0 to 4 scale), weighted by the area of involvement.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)	CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	86	90	76	166
Units: percentage of participants
number (confidence interval 95%)
percentage of participants	15.1 (7.5 to 22.7)	62.2 (52.2 to 72.2)	60.5 (49.5 to 71.5)	61.4 (54 to 68.8)

Statistical Analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

252

Analysis specification

Pre-specified

Analysis type

P-value

< 0.001 ^[8]

Method

Wald-test, 2-sided

Parameter type

Mean difference (final values)

Point estimate

46.3

Confidence interval

level

95%

sides

2-sided

lower limit

35.7

upper limit

56.9

Notes
[8] - Difference of Certolizumab Pegol 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using a standard two-sided Wald asymptotic test with a 5 % alpha level.

Secondary: Change From Baseline in Modified Total Sharp Score (mTSS) at Week 48

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End point title

Change From Baseline in Modified Total Sharp Score (mTSS) at Week 48

End point description

Van der Heijde modified Total Sharp Score (mTSS) is a methodology to assess the degree of joint damage by quantifying the extent of bone erosions and joint space narrowing for 64 and 52 joints, respectively, with higher scores representing greater damage. mTSS (bone erosions) ranges from 0 (best possible outcome) to 320 (worst possible outcome); mTSS (joint space narrowing) ranges from 0 (best possible outcome) to 208 (worst possible outcome); and total score ranges from 0 (best possible outcome) to 528 (worst possible outcome). For the analysis of this outcome measure, the change from Baseline to Week 48 was imputed using the median change from Baseline among all subjects for those subjects, which had less than 2 radiographs. The post-hoc analysis presented here is based on the subgroup of subjects which had a Baseline mTSS value greater than 6.

End point type

Secondary

End point timeframe

From Baseline to Week 48

End point values	Placebo (Randomized Set)	CZP 200 mg Q2W (Randomized Set)	CZP 400 mg Q4W (Randomized Set)	CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)
Number of subjects analysed	136	138	135	273
Units: units on a scale
least squares mean (confidence interval 95%)
Predefined results: Overall	0.32 (0.1 to 0.55)	0.15 (-0.07 to 0.37)	0.11 (-0.12 to 0.34)	0.13 (-0.05 to 0.31)
Post-hoc results: Basel. mTSS > 6 (n=61,65,65,130)	0.78 (0.31 to 1.25)	0.31 (-0.15 to 0.77)	0.22 (-0.24 to 0.67)	0.26 (-0.09 to 0.62)

Statistical analysis 1

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the predefined analysis.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

409

Analysis specification

Pre-specified

Analysis type

P-value

= 0.127 ^[9]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.43

upper limit

0.05

Variability estimate

Standard error of the mean

Dispersion value

0.12

Notes
[9] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

Statistical Analysis 2

Statistical analysis description

A hierarchical test procedure was applied to protect the overall significance level for the multiplicity of dose groups and endpoints. Conditional on the first test being significant, the second hypothesis was tested with the same alpha level of 5 %. Statistical testing for the following hypotheses was performed only if the previous null hypothesis in the hierarchy was rejected. This is the post-hoc analysis for the subgroup 'Baseline mTSS > 6'.

Comparison groups

Placebo (Randomized Set) v CZP 200 mg Q2W and CZP 400 mg Q4W (Randomized Set)

Number of subjects included in analysis

409

Analysis specification

Pre-specified

Analysis type

P-value

= 0.048 ^[10]

Method

ANCOVA

Parameter type

Mean difference (net)

Point estimate

-0.52

Confidence interval

level

95%

sides

2-sided

lower limit

-1.04

upper limit

-0.01

Variability estimate

Standard error of the mean

Dispersion value

0.26

Notes
[10] - Difference of CZP 200 mg + 400 mg versus Placebo (and corresponding 95 % Confidence Interval and p-value) were estimated using an ANCOVA model with treatment, region and prior TNF-antagonist exposure as factors and Baseline mTSS score as a covariate.

Adverse events

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Timeframe for reporting adverse events

Adverse Events (AEs) were collected from Baseline (Week 0) over the whole Double-Blind, Dose-Blind and Open-Label Period.

Adverse event reporting additional description

PBO arm subjects shifted either at Wk 16 or 24 to CZP treatment. Thus, PBO arm had lower exposure compared to the CZP arms. The exposure imbalance across treatment arms could lead to misinterpretation & questionable conclusions comparing simple counts & percentages of AEs. Thus, AEs reported while the patient was on PBO-treatment are not included.

Assessment type

Non-systematic

Dictionary name

MedDRA

Dictionary version

14.1

Reporting group title

All CZP 200 mg Q2W

Reporting group description

This arm includes all subjects who were randomized to CZP 200 mg Q2W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 200 mg Q2W. Subjects received one injection of 200 mg CZP and one injection of Placebo every two weeks to maintain the study blind.

Reporting group title

All CZP 200 mg + 400 mg

Reporting group description

This arm shows all patients treated with Certolizumab Pegol (CZP) at least once. Hence, this arm is a combination of arm All CZP 200 mg Q2W and arm All CZP 400 mg Q4W.

Reporting group title

All CZP 400 mg Q4W

Reporting group description

This arm includes all subjects who were randomized to CZP 400 mg Q4W at Baseline and those subjects who escaped or were re-randomized from Placebo to CZP 400 mg Q4W. Subjects received two injections of Placebo every four weeks in between the two injections of 200 mg CZP to maintain the study blind.

Serious adverse events	All CZP 200 mg Q2W	All CZP 200 mg + 400 mg	All CZP 400 mg Q4W
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 198 (24.75%)	100 / 393 (25.45%)	51 / 195 (26.15%)
number of deaths (all causes)	3	6	3
number of deaths resulting from adverse events	0	2	2
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	1 / 198 (0.51%)	3 / 393 (0.76%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Gastrointestinal cancer metastatic
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1
Ovarian cancer
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign neoplasm of thyroid gland
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Haematoma
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombophlebitis
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Hip arthroplasty
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy, puerperium and perinatal conditions
Pregnancy
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pregnancy on contraceptive
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Sudden death
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1
Pyrexia
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Social circumstances
Pregnancy of partner
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Metrorrhagia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Genital prolapse
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine haemorrhage
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine polyp
subjects affected / exposed	0 / 198 (0.00%)	2 / 393 (0.51%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vulvar dysplasia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Hypoxia
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemoptysis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung infiltration
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleurisy
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	3 / 198 (1.52%)	3 / 393 (0.76%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Bipolar I disorder
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute stress disorder
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post-traumatic stress disorder
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Hepatic enzyme increased
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Concussion
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial rupture
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 198 (0.00%)	2 / 393 (0.51%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Animal bite
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anastomotic complication
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Coronary artery thrombosis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	2 / 198 (1.01%)	2 / 393 (0.51%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocarditis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0
Nervous system disorders
Cerebrovascular accident
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dysgraphia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Formication
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paralysis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Epilepsy
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoaesthesia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Speech disorder
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Splenomegaly
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Thrombocytopenia
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	2 / 2	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Tinnitus
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diplopia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypoaesthesia oral
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Biliary colic
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	1 / 198 (0.51%)	3 / 393 (0.76%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	0 / 198 (0.00%)	2 / 393 (0.51%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 0	1 / 2	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Biliary dyskinesia
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct obstruction
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Cutaneous lupus erythematosus
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	2 / 2	2 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin ulcer
subjects affected / exposed	3 / 198 (1.52%)	4 / 393 (1.02%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 4	1 / 5	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Urinary incontinence
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cyst
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus ureteric
subjects affected / exposed	0 / 198 (0.00%)	2 / 393 (0.51%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal colic
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthritis
subjects affected / exposed	2 / 198 (1.01%)	3 / 393 (0.76%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	1 / 2	1 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 198 (0.00%)	2 / 393 (0.51%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lupus-like syndrome
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 198 (0.51%)	4 / 393 (1.02%)	3 / 195 (1.54%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psoriatic arthropathy
subjects affected / exposed	5 / 198 (2.53%)	8 / 393 (2.04%)	3 / 195 (1.54%)
occurrences causally related to treatment / all	0 / 5	0 / 12	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Diverticulitis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	2 / 198 (1.01%)	2 / 393 (0.51%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis bacterial
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Herpes zoster
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 198 (0.51%)	4 / 393 (1.02%)	3 / 195 (1.54%)
occurrences causally related to treatment / all	0 / 1	3 / 5	3 / 4
deaths causally related to treatment / all	0 / 0	2 / 2	2 / 2
Bronchitis
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchopneumonia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
HIV infection
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	1 / 1	1 / 1
Staphylococcal abscess
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	2 / 198 (1.01%)	2 / 393 (0.51%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 2	1 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyoderma streptococcal
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Latent tuberculosis
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper respiratory tract infection
subjects affected / exposed	1 / 198 (0.51%)	2 / 393 (0.51%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	1 / 1	2 / 2	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 198 (0.51%)	3 / 393 (0.76%)	2 / 195 (1.03%)
occurrences causally related to treatment / all	1 / 1	2 / 3	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	1 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Diabetes mellitus
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obesity
subjects affected / exposed	0 / 198 (0.00%)	1 / 393 (0.25%)	1 / 195 (0.51%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyperglycaemia
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dehydration
subjects affected / exposed	1 / 198 (0.51%)	1 / 393 (0.25%)	0 / 195 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	All CZP 200 mg Q2W	All CZP 200 mg + 400 mg	All CZP 400 mg Q4W
Total subjects affected by non serious adverse events
subjects affected / exposed	158 / 198 (79.80%)	311 / 393 (79.13%)	153 / 195 (78.46%)
Investigations
Alanine aminotransferase increased
subjects affected / exposed	17 / 198 (8.59%)	32 / 393 (8.14%)	15 / 195 (7.69%)
occurrences all number	23	48	25
Blood creatine phosphokinase increased
subjects affected / exposed	15 / 198 (7.58%)	28 / 393 (7.12%)	13 / 195 (6.67%)
occurrences all number	28	53	25
Aspartate aminotransferase increased
subjects affected / exposed	9 / 198 (4.55%)	20 / 393 (5.09%)	11 / 195 (5.64%)
occurrences all number	13	30	17
Gamma-glutamyltransferase increased
subjects affected / exposed	8 / 198 (4.04%)	20 / 393 (5.09%)	12 / 195 (6.15%)
occurrences all number	11	26	15
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	15 / 198 (7.58%)	24 / 393 (6.11%)	9 / 195 (4.62%)
occurrences all number	21	31	10
Vascular disorders
Hypertension
subjects affected / exposed	30 / 198 (15.15%)	46 / 393 (11.70%)	16 / 195 (8.21%)
occurrences all number	33	53	20
Nervous system disorders
Headache
subjects affected / exposed	18 / 198 (9.09%)	35 / 393 (8.91%)	17 / 195 (8.72%)
occurrences all number	19	39	20
Dizziness
subjects affected / exposed	5 / 198 (2.53%)	15 / 393 (3.82%)	10 / 195 (5.13%)
occurrences all number	5	15	10
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	15 / 198 (7.58%)	26 / 393 (6.62%)	11 / 195 (5.64%)
occurrences all number	20	35	15
Abdominal pain
subjects affected / exposed	12 / 198 (6.06%)	21 / 393 (5.34%)	9 / 195 (4.62%)
occurrences all number	13	23	10
Abdominal pain upper
subjects affected / exposed	14 / 198 (7.07%)	19 / 393 (4.83%)	5 / 195 (2.56%)
occurrences all number	16	25	9
Nausea
subjects affected / exposed	10 / 198 (5.05%)	18 / 393 (4.58%)	8 / 195 (4.10%)
occurrences all number	11	20	9
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	8 / 198 (4.04%)	22 / 393 (5.60%)	14 / 195 (7.18%)
occurrences all number	9	23	14
Oropharyngeal pain
subjects affected / exposed	6 / 198 (3.03%)	16 / 393 (4.07%)	10 / 195 (5.13%)
occurrences all number	6	19	13
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	22 / 198 (11.11%)	41 / 393 (10.43%)	19 / 195 (9.74%)
occurrences all number	31	52	21
Rash
subjects affected / exposed	10 / 198 (5.05%)	19 / 393 (4.83%)	9 / 195 (4.62%)
occurrences all number	16	25	9
Psychiatric disorders
Depression
subjects affected / exposed	11 / 198 (5.56%)	20 / 393 (5.09%)	9 / 195 (4.62%)
occurrences all number	12	24	12
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	24 / 198 (12.12%)	46 / 393 (11.70%)	22 / 195 (11.28%)
occurrences all number	28	54	26
Psoriatic arthropathy
subjects affected / exposed	24 / 198 (12.12%)	39 / 393 (9.92%)	15 / 195 (7.69%)
occurrences all number	41	64	23
Arthralgia
subjects affected / exposed	20 / 198 (10.10%)	38 / 393 (9.67%)	18 / 195 (9.23%)
occurrences all number	28	56	28
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	44 / 198 (22.22%)	93 / 393 (23.66%)	49 / 195 (25.13%)
occurrences all number	81	154	73
Nasopharyngitis
subjects affected / exposed	45 / 198 (22.73%)	87 / 393 (22.14%)	42 / 195 (21.54%)
occurrences all number	87	178	91
Pharyngitis
subjects affected / exposed	24 / 198 (12.12%)	51 / 393 (12.98%)	27 / 195 (13.85%)
occurrences all number	44	81	37
Bronchitis
subjects affected / exposed	28 / 198 (14.14%)	50 / 393 (12.72%)	22 / 195 (11.28%)
occurrences all number	36	65	29
Urinary tract infection
subjects affected / exposed	13 / 198 (6.57%)	39 / 393 (9.92%)	26 / 195 (13.33%)
occurrences all number	18	53	35
Sinusitis
subjects affected / exposed	19 / 198 (9.60%)	32 / 393 (8.14%)	13 / 195 (6.67%)
occurrences all number	32	65	33
Gastroenteritis
subjects affected / exposed	14 / 198 (7.07%)	22 / 393 (5.60%)	8 / 195 (4.10%)
occurrences all number	18	26	8
Oral herpes
subjects affected / exposed	10 / 198 (5.05%)	21 / 393 (5.34%)	11 / 195 (5.64%)
occurrences all number	25	43	18
Influenza
subjects affected / exposed	13 / 198 (6.57%)	21 / 393 (5.34%)	8 / 195 (4.10%)
occurrences all number	15	24	9
Tonsillitis
subjects affected / exposed	11 / 198 (5.56%)	19 / 393 (4.83%)	8 / 195 (4.10%)
occurrences all number	11	23	12
Rhinitis
subjects affected / exposed	10 / 198 (5.05%)	19 / 393 (4.83%)	9 / 195 (4.62%)
occurrences all number	11	20	9
Latent tuberculosis
subjects affected / exposed	6 / 198 (3.03%)	18 / 393 (4.58%)	12 / 195 (6.15%)
occurrences all number	6	18	12
Viral infection
subjects affected / exposed	9 / 198 (4.55%)	16 / 393 (4.07%)	7 / 195 (3.59%)
occurrences all number	12	19	7

More information

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Were there any global substantial amendments to the protocol? Yes

23 Nov 2009

The protocol was amended to adapt to the most recent scientific developments in the field. In addition, the Sponsor Study Physician information was updated, a few typographical errors were corrected, and some clarifications were made to the protocol text. The original final PsA001 protocol (25 Sep 2009) was approved internally by the Sponsor; however, Protocol Amendment 1 (23 Nov 2009) was the first version of the protocol to be submitted to any regulatory health authority. The following changes were made throughout the protocol: - The Sponsor Study Physician information was updated - The Classification Criteria for Psoriatic Arthritis (CASPAR) were added to the inclusion criteria - Leflunomide was added to the list of allowed DMARDs, and hydroxychloroquine (HCQ) and DMARD combinations were now prohibited - The effect of CZP on axial involvement in a subgroup of affected subjects (BASDAI ≥4) at Baseline was added as another secondary objective - Measurement of human leukocyte antigen B27 (HLA-B27) at Baseline was included - Permission was given for samples collected for measurement of CZP plasma concentration to be possibly used for exploratory biomarker (Dickkopf-related protein 1 [DKK1] and sclerostin) research - The swollen joint count and tender joint count assessments were changed from the 76/78 joints to the 66/68 joints evaluation - Clarification that assessment of arthritis should include consideration of both joint and skin components in both the Patient’s and Physician’s Global Assessments of Disease Activity (PtGADA and PhGADA, respectively) was added - Clarification that the PhGADA (Likert Scale) was to be used only for the Psoriatic Arthritis Response Criteria (PsARC) assessment was added - Clarification that PsA history included relevant family history and prior and concomitant medication history was added

21 Apr 2010

The following changes were made throughout the protocol: - FAS was replaced by the RS for the primary efficacy analyses. - The SAP was adjusted for multiple endpoints. A hierarchical test procedure was applied to protect the overall significance level of the multiplicity of dose groups and endpoints with a predefined order of hypotheses testing. - Assessment of subjects with a PhGAP rating of “clear” or “almost clear” was added as a secondary endpoint to evaluate psoriatic skin lesions. - The specification that vital signs were to be performed within 15 minutes prior to dosing was removed. - A definition of PASI assessments was added. Clarification was added that the dactylitis assessment was to be performed using the LDI basic according to Healy and Helliwell (2007) and Helliwell et al (2005). - Clarification was added that the enthesitis assessment was to be performed on the elbows, knees, and heels. - Description of the mNAPSI assessment was modified in accordance with Cassell et al, 2007. - Clarification was added that abatacept (ABA) was both a prohibited medication (if used within 3 months prior to BL) and a prohibited concomitant and and rescue treatment. - For tuberculosis (TB) testing, inconsistencies in visit referencing (eg, BL) with regards to purified protein derivative (PPD) tests were corrected to reference the Screening Visit. - Clarification that the cited liver function tests >2x ULN, creatinine>ULN, or white blood cells (WBCs) <3.0x109/L represent examples of clinically significant laboratory abnormalities, which would exclude subject entry into the study, was added to the appropriate exclusion criterion. - Clarification was added that 1 rescreening of subjects with latent TB who were unable to complete a minimum of 4 weeks of TB therapy within the Screening Period was permitted. - Clarification was added that if the Elispot was neg. at Screening, it would be repeated at W48 and W96 for subjects with a previously negative Elispot test result

22 Nov 2010

The protocol was amended to increase the approximate number of centers participating in this study and the approximate number of subjects who would be screened because of a higher than expected screen failure rate. In addition, Sponsor personnel and the corresponding contact information were updated. Administrative changes for internal consistency were also implemented. The following changes were made throughout the protocol: - The approximate number of subjects who were to be screened was increased from 500 to 700 - The approximate number of centers participating in the study was increased from 100 to 130 - Based on previous feedback from the FDA, all randomized subjects must be used for primary analysis; therefore, the statement that 375 subjects would be available for the primary efficacy analyses was deleted

30 Jan 2012

The protocol was amended to comply with new FDA Safety Reporting Requirements (Food and Drug Administration, Guidance for Industry, 2010) and the corresponding change to the UCB Protocol Template, language was added to the Assessment of Safety Section to clarify procedures for reporting relatedness of an serious adverse event (SAE) and to define anticipated SAEs. In addition, the name of the Sponsor, Sponsor personnel, and the corresponding contact information were updated. Administrative changes for internal consistency were also implemented. The following changes were made throughout the protocol: - For the assessment of socioprofessional status, housing status of the subject was not obtained by site personnel - Additional guidance to Investigators was provided for including the casual relationship of study medication between an SAE and study medication when completing the SAE report form - Anticipated SAEs were identified

25 Jan 2013

The protocol was amended to implement the extension of the Open-Label Treatment Period for an additional 58 weeks. The following changes were made throughout the protocol: - A new Clinical Project Manager was identified. - Wording regarding the extension of the Open-Label Treatment Period, additional BSA assessments, and new TB standards were added. - The list of biomarkers that may have been analyzed was updated. - Visit scheduling of Week 158 (Completion/Withdrawal Visit) was shifted to Week 216 and the last dosing visit of Week 156 was changed to occur at Week 214 for the 200mg Q2W regimen and Week 212 for the 400mg Q4W regimen. The regular last site visit and the final evaluation visit were combined to reduce the amount of investigations and visits. - Chest x-ray was requested additionally at Week 156 and at the Completion Visit Week 216/ Withdrawal. - Hand and foot x-rays were added at Week 168 and at Withdrawal Visit if hand and foot x-ray was performed more than 8 weeks prior to Withdrawal Visit. - Assessment of BSA und PASI for all subjects at Weeks 156, 168, 180, 192, 204, and 216/ Withdrawal. - PPD and interferon-gamma release assay (IGRA) tests were requested additionally at Weeks 48, 96, 156, and Week 216/ Withdrawal. - Definition of minimal disease activity was added. - The adverse event (AE) of interest section was updated to be consistent with current reporting requirements.

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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