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Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy and Safety Study of Two Doses of Apremilast (CC-10004) in Subjects with Active Psoriatic Arthritis and a Qualifying Psoriasis Lesion

Summary
EudraCT number	2010-019941-24
Trial protocol	LT SK FI GB DE ES IT
Global end of trial date	09 Feb 2017

Results information
Results version number	v1(current)
This version publication date	24 Feb 2018
First version publication date	24 Feb 2018
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

CC-10004-PSA-004

ISRCTN number

US NCT number

NCT01212770

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

Clinical Trial Disclosure, Celgene Corporation, 01 8882601599, ClinicalTrialDisclosure@Celgene.com

Scientific contact

Nikolay Delev, Celgene Corporation, 01 18882601599, ndelev@celgene.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 Jun 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Feb 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of the study was to evaluate the clinical efficacy of 2 doses of apremilast (20 mg or 30 mg orally twice daily [BID]), compared with placebo (PBO), on the signs and symptoms of psoriatic arthritis (PsA) after 16 weeks administration.

Protection of trial subjects

Patient Confidentiality, Personal Data Protection and Biomarker Consent. This study was conducted in accordance with the guidelines of current Good Clinical Practice including the archiving of essential documents.

Background therapy

Evidence for comparator

Actual start date of recruitment

30 Sep 2010

Long term follow-up planned

Yes

Long term follow-up rationale

Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research

Long term follow-up duration

5 Years

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Finland: 7

Country: Number of subjects enrolled

France: 6

Country: Number of subjects enrolled

Germany: 12

Country: Number of subjects enrolled

Italy: 9

Country: Number of subjects enrolled

Lithuania: 27

Country: Number of subjects enrolled

Poland: 111

Country: Number of subjects enrolled

Romania: 25

Country: Number of subjects enrolled

Slovakia: 9

Country: Number of subjects enrolled

Spain: 16

Country: Number of subjects enrolled

Switzerland: 6

Country: Number of subjects enrolled

United Kingdom: 4

Country: Number of subjects enrolled

United States: 130

Country: Number of subjects enrolled

Canada: 34

Country: Number of subjects enrolled

Australia: 44

Country: Number of subjects enrolled

Korea, Republic of: 12

Country: Number of subjects enrolled

Russian Federation: 53

Worldwide total number of subjects

505

EEA total number of subjects

226

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)

459

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study was conducted at 78 study centers in 16 countries.

Screening details

This study consisted of a 24-week randomized, double-blind, placebo-controlled phase, a 28-week randomized, double-blind active treatment phase and a 4-year open-label safety phase, for an overall study duration of 5 years.

Period 1 title

Placebo-controlled Phase (Week 0 - 24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

Blinding to treatment assignment was maintained at all sites until after the Week 52 database lock at Year 1, after all Week 52 analyses were completed and the results were released. At that time, active medication was provided. The blind was otherwise not to be broken during the study unless, in the opinion of the doctor, it was necessary to safely treat the subject.

Are arms mutually exclusive

Yes

Placebo

Arm description

Participants initially randomized to receive placebo tablets twice daily (BID) in the 24-week placebo-controlled phase. Participants who did not have at least 20% improvement in swollen and tender joint counts at Week 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily (early escape).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo tablets (identical in appearance to apremilast) twice daily.

Apremilast 20 mg

Arm description

Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Participants initially randomized to 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 1	Placebo	Apremilast 20 mg	Apremilast 30 mg
Started	169	169	167
Received Treatment	169	169	167
Completed Week 16	156	157	156
Early Escape at Week 16	97 ^[1]	76 ^[2]	53 ^[3]
Completed	146	147	145
Not completed	23	22	22
Consent withdrawn by subject	3	4	1
Adverse event, non-fatal	10	12	8
Miscellaneous	3	1	2
Lost to follow-up	1	-	3
Lack of efficacy	6	5	7
Protocol deviation	-	-	1

Notes
[1] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
[2] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.
[3] - The number of subjects at this milestone seems inconsistent with the number of subjects in the arm. It is expected that the number of subjects will be greater than, or equal to the number that completed, minus those who left.
Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Period 2 title

Active Treatment Phase (Weeks 25 - 52)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

Are arms mutually exclusive

Yes

Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otzela

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Participants initially randomized to 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase continued receiving 30 mg apremilast tablets twice daily in the active treatment / long-term safety phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo / Apremilast 20 mg EE

Arm description

Participants initially randomized to placebo twice daily were re-randomized due to early escape (EE) at Week 16 to receive 20 mg apremilast twice daily in the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo / Apremilast 20 mg XO

Arm description

Participants initially randomized to receive placebo twice daily were re-randomized at Week 24 (XO) to receive 20 mg apremilast tablets twice daily in the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo / Apremilast 30 mg EE

Arm description

Participants initially randomized to placebo twice daily were re-randomized due to early escape at Week 16 to receive 30 mg apremilast tablets twice daily in the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo / Apremilast 30 mg XO

Arm description

Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 to receive 30 mg apremilast twice daily in the active treatment phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 2 ^[4]	Apremilast 20 mg	Apremilast 30 mg	Placebo / Apremilast 20 mg EE	Placebo / Apremilast 20 mg XO	Placebo / Apremilast 30 mg EE	Placebo / Apremilast 30 mg XO
Started	139	138	43	25	47	25
Completed	120	126	32	23	44	23
Not completed	19	12	11	2	3	2
Consent withdrawn by subject	6	3	3	1	1	1
Adverse event, non-fatal	6	2	2	-	-	1
Unspecified	-	1	1	-	-	-
Lost to follow-up	-	1	-	-	-	-
Lack of efficacy	7	5	4	1	2	-
Protocol deviation	-	-	1	-	-	-

Notes
[4] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Period 3 title

Long-term Safety Phase (Year 2)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo/Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo/Apremilast 30 mg

Arm description

Participants initially randomized to placebo tablets BID during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg tablets twice daily in the active treatment / long-term safety phase.

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 3 ^[5]	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	111	121	51	64
Completed	88	106	42	50
Not completed	23	15	9	14
Consent withdrawn by subject	9	3	4	4
Adverse event, non-fatal	3	3	-	2
Miscellaneous	2	1	-	1
Non-compliance	1	-	-	-
Lost to follow-up	2	1	1	1
Lack of efficacy	6	7	4	6

Notes
[5] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Period 4 title

Long-term Safety Phase (Year 3)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo/Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo/Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 4 ^[6]	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	87	105	42	49
Completed	76	94	35	44
Not completed	11	11	7	5
Consent withdrawn by subject	3	4	1	1
Adverse event, non-fatal	2	2	2	1
Miscellaneous	2	1	1	1
Lost to follow-up	1	-	-	-
Lack of efficacy	3	4	2	2
Protocol deviation	-	-	1	-

Notes
[6] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Period 5 title

Long-term Safety Phase (Year 4)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo/Apremilast 20 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo/Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 5	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	76	94	35	44
Completed	71	83	32	42
Not completed	6	11	3	2
Consent withdrawn by subject	2	3	-	-
Adverse event, non-fatal	1	1	-	1
Miscellaneous	1	-	-	1
Non-compliance with study drug	1	1	1	-
Lost to follow-up	-	1	-	-
Lack of efficacy	1	5	2	-
Joined	1	0	0	0
1 subject not counted in year 4	1	-	-	-

Period 6 title

Long-term Safety Phase (Year 5)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apremilast 20 mg

Arm description

Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast tablets twice daily in the active treatment / long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Placebo/Apremilast 20 mg

Arm description

Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast tablets twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg tablets twice daily in active treatment/long-term safety phase. (After 30 mg apremilast BID was identified as the optimal dose, all participants receiving 20 mg apremilast BID were switched to the 30 mg apremilast BID dose).

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 20 mg tablets twice daily

Placebo/Apremilast 30 mg

Arm description

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Apremilast 30 mg tablets twice daily

Number of subjects in period 6 ^[7]	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	70	83	32	42
Completed	68	72	30	41
Not completed	2	11	2	1
Adverse event, serious fatal	-	-	1	-
Consent withdrawn by subject	2	1	1	-
Adverse event, non-fatal	-	2	-	1
Miscellaneous	-	3	-	-
Missing	-	1	-	-
Lack of efficacy	-	4	-	-

Notes
[7] - 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: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Apremilast 20 mg

Reporting group description

Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

Reporting group title

Apremilast 30 mg

Reporting group description

Participants initially randomized to 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.

Reporting group values	Placebo	Apremilast 20 mg	Apremilast 30 mg	Total
Number of subjects	169	169	167	505
Age categorical
Units: Subjects
In utero	0	0	0	0
Preterm newborn infants (gestational age < 37 wks)	0	0	0	0
Newborns (0-27 days)	0	0	0	0
Infants and toddlers (28 days-23 months)	0	0	0	0
Children (2-11 years)	0	0	0	0
Adolescents (12-17 years)	0	0	0	0
Adults (18-64 years)	155	152	152	459
From 65-84 years	14	17	15	46
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	49.5 ( 11.64 )	49.6 ( 12.10 )	49.9 ( 11.38 )	-
Gender, Male/Female
Units: Subjects
Female	91	90	88	269
Male	78	79	79	236
Duration of psoriatic arthritis
Units: years
arithmetic mean (standard deviation)	6.78 ( 6.463 )	7.74 ( 7.690 )	7.48 ( 7.646 )	-

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Apremilast 20 mg

Reporting group description

Participants initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

Reporting group title

Apremilast 30 mg

Reporting group description

Participants initially randomized to 30 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.

Reporting group title

Apremilast 20 mg

Reporting group description

Reporting group title

Apremilast 30 mg

Reporting group description

Reporting group title

Placebo / Apremilast 20 mg EE

Reporting group description

Participants initially randomized to placebo twice daily were re-randomized due to early escape (EE) at Week 16 to receive 20 mg apremilast twice daily in the active treatment phase.

Reporting group title

Placebo / Apremilast 20 mg XO

Reporting group description

Participants initially randomized to receive placebo twice daily were re-randomized at Week 24 (XO) to receive 20 mg apremilast tablets twice daily in the active treatment phase.

Reporting group title

Placebo / Apremilast 30 mg EE

Reporting group description

Participants initially randomized to placebo twice daily were re-randomized due to early escape at Week 16 to receive 30 mg apremilast tablets twice daily in the active treatment phase.

Reporting group title

Placebo / Apremilast 30 mg XO

Reporting group description

Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 to receive 30 mg apremilast twice daily in the active treatment phase.

Reporting group title

Apremilast 20 mg

Reporting group description

Reporting group title

Apremilast 30 mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg

Reporting group description

Reporting group title

Apremilast 20 mg

Reporting group description

Reporting group title

Apremilast 30 mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg

Reporting group description

Reporting group title

Apremilast 20 mg

Reporting group description

Reporting group title

Apremilast 30 mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg

Reporting group description

Reporting group title

Apremilast 20 mg

Reporting group description

Reporting group title

Apremilast 30 mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg

Reporting group description

Subject analysis set title

Placebo /Apremilast 20 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subjects initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 20 mg twice daily at Week 16 or Week 24 and continued receiving apremilast 20 mg twice daily in the active treatment/long-term safety phase.

Subject analysis set title

Placebo/Apremilast 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subjects initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg twice daily at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily in the active treatment/long-term safety phase.

Subject analysis set title

Apremilast 20 mg

Subject analysis set type

Full analysis

Subject analysis set description

Subjects initially randomized to 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 20 mg apremilast twice daily in the active treatment/long-term safety phase.

Subject analysis set title

Apremilast 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued receiving 30 mg apremilast twice daily in the active treatment/long-term safety phase.

Subject analysis set title

Apremilast 20 mg (Pre-switch)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received apremilast 20 mg twice daily regardless of when the apremilast exposure started (at Week 0, 16 or 24). Only the TEAEs that occurred during apremilast 20 mg BID treatment (before the switch to 30 mg apremilast) were included

Subject analysis set title

Apremilast 20 mg/30 mg (Post-switch)

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who switched from apremilast 20 mg twice daily to apremilast 30 mg twice daily. Only the TEAEs that occurred during APR 30 mg BID treatment were included.

Subject analysis set title

Apremilast 30 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Subjects who received apremilast 30 mg twice daily, regardless of when the apermilast-exposure started (at Week 0, 16 or 24).

Subject analysis set title

Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received placebo tablets twice daily in the 24-week placebo-controlled phase.

Subject analysis set title

Apremilast 20 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

Subject analysis set title

Apremilast 30 mg

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase.

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 16

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End point title

Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 16

End point description

A subject was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Full analysis set (FAS) = subjects randomized as specified per protocol; subjects who were randomized in error and did not receive any dose of study drug were excluded. Subjects who withdrew early who did not have sufficient data for a determination of response status at Week 16 were counted as non-responders

End point type

Primary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	18.3	28.4	40.7

Statistical Analysis 1

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across 4 strata of baseline DMARD use by ≥ 3% BSA psoriasis involvement at baseline with the CMH weights. The 95% CI is based on a normal approximation to the weighted average

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

< 0.0001 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

22.3

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

31.6

Notes
[1] - The percentage of participants with an ACR20 response was compared using a Cochran-Mantel- Haenszel (CMH) test. The Hochberg procedure was used to maintain the Type 1 error at the 0.05 significance level. The results were considered statistically significant if both the 30 mg apremilast dose versus placebo comparison and the 20 mg versus placebo comparison were statistically significant at the 0.05 significance level, or one of the comparisons was statistically significant at the 0.025 level.
[2] - 2-sided p-value is based on the CMH test adjusting for baseline disease modifying antirheumatic drug (DMARD) use and ≥ 3% body surface area (BSA) psoriasis involvement at baseline.

Statistical Analysis 2

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across 4 strata of baseline DMARD use by ≥ 3% BSA psoriasis involvement at baseline with the CMH weights.

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority ^[3]

P-value

= 0.0295 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.1

upper limit

18.6

Notes
[3] - In order to maintain the Type 1 error at the 0.05 significance level, the Hochberg procedure was to be used. The results of the endpoint were to be considered statistically significant if both the 30 mg apremilast dose versus placebo comparison and the 20 mg versus placebo comparison were statistically significant at the 0.05 significance level, or one of the comparisons was statistically significant at the 0.025 level.
[4] - 2-sided p-value is based on the CMH test adjusting for baseline disease modifying antirheumatic drug (DMARD) use and ≥ 3% body surface area (BSA) psoriasis involvement at baseline.

Secondary: Change From Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16

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End point title

Change From Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16

End point description

The Health Assessment Questionnaire - Disability Index is a patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. FAS population. Subjects with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF imputation was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	163	163	160
Units: units on a scale
least squares mean (standard error)	-0.065 ( 0.0335 )	-0.131 ( 0.0337 )	-0.192 ( 0.0339 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0073 ^[6]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.127

Confidence interval

level

95%

sides

2-sided

lower limit

-0.22

upper limit

-0.034

Notes
[5] - Pairwise comparisons (30 mg vs placebo and 20 mg vs placebo) were conducted conditional on the primary endpoint results. If the primary endpoint was statistically significant for both apremilast dose groups, pairwise comparisons for the HAQ-DI were to be evaluated at the 0.05 level using the Hochberg procedure. If only one apremilast dose was statistically significant, then only the comparison between that apremilast dose and placebo was conducted for the HAQ-DI score, at the 0.025 level.
[6] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Apremilast 20 mg v Placebo

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.1619 ^[8]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.066

Confidence interval

level

95%

sides

2-sided

lower limit

-0.158

upper limit

0.027

Notes
[7] - Pairwise comparisons (30 mg vs placebo and 20 mg vs placebo) were conducted conditional on the primary endpoint results. If the primary endpoint was statistically significant for both apremilast dose groups, pairwise comparisons for the HAQ-DI were to be evaluated at the 0.05 level using the Hochberg procedure. If only one apremilast dose was statistically significant, then only the comparison between that apremilast dose and placebo was conducted for the HAQ-DI score, at the 0.025 level.
[8] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate

Secondary: Percentage of Participants With an ACR 20 Response at Week 24

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End point title

Percentage of Participants With an ACR 20 Response at Week 24

End point description

Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. FAS population; subjects who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	15.4	26.6	31.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0007 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

15.5

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

24.3

Notes
[9] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above. Adjusted difference is the weighted average of the treatment differences across 4 strata of baseline DMARD use by ≥ 3% BSA psoriasis involvement at baseline with the CMH weights. The 95% CI is based on a normal approximation to the weighted average.
[10] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.011 ^[12]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

11.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.7

upper limit

19.5

Notes
[11] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above. Adjusted difference is the weighted average of the treatment differences across 4 strata of baseline DMARD use by ≥ 3% BSA psoriasis involvement at baseline with the CMH weights. The 95% CI is based on a normal approximation to the weighted average.
[12] - 2-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

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

Top of page

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 patient-reported questionnaire consisting of 20 questions referring to eight domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. Subjects with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	163	164	161
Units: units on a scale
least squares mean (standard error)	-0.053 ( 0.0350 )	-0.137 ( 0.0351 )	-0.192 ( 0.0353 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.005 ^[14]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.139

Confidence interval

level

95%

sides

2-sided

lower limit

-0.236

upper limit

-0.042

Notes
[13] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[14] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.086 ^[16]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.084

Confidence interval

level

95%

sides

2-sided

lower limit

-0.181

upper limit

0.012

Notes
[15] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[16] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16

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End point title

Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16

End point description

The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	162	162	160
Units: units on a scale
least squares mean (standard error)	1.14 ( 0.589 )	2.29 ( 0.592 )	3.47 ( 0.594 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0053 ^[18]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.32

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

3.95

Notes
[17] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[18] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.1658 ^[20]

Method

ANCOVA

Parameter type

LS mean Difference

Point estimate

1.15

Confidence interval

level

95%

sides

2-sided

lower limit

-0.48

upper limit

2.77

Notes
[19] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[20] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16

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End point title

Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16

End point description

Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm visual Analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	27.2	37.9	52.7

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

< 0.0001 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

25.4

Confidence interval

level

95%

sides

2-sided

lower limit

15.5

upper limit

35.3

Notes
[21] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[22] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use and ≥ 3% BSA psoriasis involvement at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.0372 ^[24]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

10.4

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

Notes
[23] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[24] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use and ≥ 3% BSA psoriasis involvement at baseline.

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 16

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End point title

Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 16

End point description

The percentage of participants with Baseline psoriasis body surface area (BSA) involvement ≥ 3% who achieved 75% or greater improvement from Baseline in Psoriasis Area and Severity Index (PASI) score after 16 weeks of treatment. The Psoriasis Area and Severity Index (PASI) score is a combination of the intensity of psoriasis, assessed by erythema (reddening), induration (plaque thickness) and desquamation (scaling) scored on a scale from 0 (none) to 4 (very severe), together with the percentage of the area affected, rated on a scale from 0 (no involvement) to 6 (90% to 100% involvement). PASI scoring is performed at four body areas, the head, arms, trunk, and legs. The total PASI score ranges from 0 to 72. The higher the total score, the more severe the disease. FAS population with BSA ≥3%; LOCF was used. Participants who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	89	91	90
Units: percentage of participants
number (not applicable)	7.9	20.9	22.2

Statistical Analysis 1

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across 2 strata of baseline DMARD with the CMH weights. The 95% CI is based on a normal approximation to the weighted average.

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.0062 ^[26]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

14.6

Confidence interval

level

95%

sides

2-sided

lower limit

4.5

upper limit

24.8

Notes
[25] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[26] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across 2 strata of baseline DMARD with the CMH weights. The 95% CI is based on a normal approximation to the weighted average.

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority ^[27]

P-value

= 0.0134 ^[28]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

23.1

Notes
[27] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[28] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Secondary: Change from Baseline in Patient’s Assessment of Pain at Week 16

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End point title

Change from Baseline in Patient’s Assessment of Pain at Week 16

End point description

The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included; LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	164	163	161
Units: mm
least squares mean (standard error)	-4.9 ( 1.79 )	-8.6 ( 1.80 )	-12.7 ( 1.81 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

P-value

= 0.0021 ^[30]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-7.8

Confidence interval

level

95%

sides

2-sided

lower limit

-12.8

upper limit

-2.9

Notes
[29] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[30] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

P-value

= 0.1482 ^[32]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

1.3

Notes
[31] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above.
[32] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16

Top of page

End point title

Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16

End point description

The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) and at least 1 postbaseline value at or prior to Week 16 are included; LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	106	93	107
Units: units on a scale
least squares mean (standard error)	-0.7 ( 0.27 )	-0.7 ( 0.29 )	-1.0 ( 0.27 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5349 ^[33]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.2

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.5

Notes
[33] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8231 ^[34]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.9

Notes
[34] - Based on an ANCOVA model with treatment group, baseline DMARD use and ≥ 3% BSA psoriasis involvement as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Dactylitis Severity Score at Week 16

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End point title

Change From Baseline in Dactylitis Severity Score at Week 16

End point description

Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	67	70	76
Units: units on a scale
least squares mean (standard error)	-1.3 ( 0.34 )	-1.7 ( 0.33 )	-2.1 ( 0.32 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.072 ^[35]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

0.1

Notes
[35] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

137

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3641 ^[36]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

0.5

Notes
[36] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 16

Top of page

End point title

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 16

End point description

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	159	154	156
Units: units on a scale
least squares mean (standard error)	-2.76 ( 0.869 )	-4.61 ( 0.886 )	-7.70 ( 0.881 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[37]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.94

Confidence interval

level

95%

sides

2-sided

lower limit

-7.34

upper limit

-2.53

Notes
[37] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

313

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1325 ^[38]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.85

Confidence interval

level

95%

sides

2-sided

lower limit

-4.27

upper limit

0.56

Notes
[38] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 16

Top of page

End point title

Change From Baseline in the Disease Activity Score (DAS28) at Week 16

End point description

The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the distal interphalangeal (DIP) joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	163	160	160
Units: units on a scale
least squares mean (standard error)	-0.28 ( 0.084 )	-0.54 ( 0.085 )	-0.74 ( 0.085 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[39]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

-0.24

Notes
[39] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0237 ^[40]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

-0.04

Notes
[40] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16

Top of page

End point title

Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16

End point description

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	160	160	160
Units: units on a scale
least squares mean (standard error)	1.18 ( 0.640 )	1.86 ( 0.643 )	3.72 ( 0.641 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0049 ^[41]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.54

Confidence interval

level

95%

sides

2-sided

lower limit

0.77

upper limit

4.3

Notes
[41] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

320

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4505 ^[42]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-1.09

upper limit

2.44

Notes
[42] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24

Top of page

End point title

Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	162	163	161
Units: units on a scale
least squares mean (standard error)	1.03 ( 0.581 )	2.71 ( 0.582 )	3.37 ( 0.585 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

323

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0043 ^[43]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.34

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

3.94

Notes
[43] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

325

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0404 ^[44]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.67

Confidence interval

level

95%

sides

2-sided

lower limit

0.07

upper limit

3.27

Notes
[44] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24

Top of page

End point title

Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24

End point description

Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm visual Analog scale (VAS), where 0 mm = lowest disease activity and 100 mm = highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	23.1	32.0	44.3

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[45]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

21.2

Confidence interval

level

95%

sides

2-sided

lower limit

11.5

upper limit

30.9

Notes
[45] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0661 ^[46]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

8.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.5

upper limit

Notes
[46] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 24

Top of page

End point title

Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 24

End point description

The percentage of participants with Baseline psoriasis body surface area (BSA) involvement ≥ 3% who achieved 75% or greater improvement from Baseline in Psoriasis Area and Severity Index (PASI) score after 24 weeks of treatment. The Psoriasis Area and Severity Index (PASI) score is a combination of the intensity of psoriasis, assessed by erythema (reddening), induration (plaque thickness) and desquamation (scaling) scored on a scale from 0 (none) to 4 (very severe), together with the percentage of the area affected, rated on a scale from 0 (no involvement) to 6 (90% to 100% involvement). PASI scoring is performed at four body areas, the head, arms, trunk, and legs. The total PASI score ranges from 0 to 72. The higher the total score, the more severe the disease. FAS population with BSA ≥3%; LOCF was used. Participants who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	89	91	90
Units: percentage of participants
number (not applicable)	11.2	22.2	25.6

Statistical Analysis 1

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across 2 strata of baseline DMARD use with the CMH weights. The 95% CI is based on a normal approximation to the weighted average.

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0099 ^[47]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

14.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.8

upper limit

25.7

Notes
[47] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for baseline DMARD use.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

180

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0515 ^[48]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

10.8

Confidence interval

level

95%

sides

2-sided

lower limit

0.1

upper limit

21.4

Notes
[48] - Two-sided p-value is based on the Cochran-Mantel-Haenszel test adjusting for baseline DMARD use

Secondary: Change From Baseline in Patient’s Assessment of Pain at Week 24

Top of page

End point title

Change From Baseline in Patient’s Assessment of Pain at Week 24

End point description

The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters. Full analysis set; participants with a baseline value and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	164	164	162
Units: mm
least squares mean (standard error)	-4.4 ( 1.75 )	-8.2 ( 1.76 )	-10.9 ( 1.77 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

326

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008 ^[49]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-11.4

upper limit

-1.7

Notes
[49] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1218 ^[50]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

Notes
[50] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24

Top of page

End point title

Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24

End point description

The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) and at least 1 post-baseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	106	93	107
Units: units on a scale
least squares mean (standard error)	-0.7 ( 0.29 )	-1.0 ( 0.31 )	-1.1 ( 0.29 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

213

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2761 ^[51]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

0.4

Notes
[51] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

199

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5012 ^[52]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.1

upper limit

0.6

Notes
[52] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Dactylitis Severity Score at Week 24

Top of page

End point title

Change From Baseline in Dactylitis Severity Score at Week 24

End point description

Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set. Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and at least 1 postbaseline value at or prior to Week 24 are included. LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	67	71	77
Units: units on a scale
least squares mean (standard error)	-1.3 ( 0.35 )	-1.7 ( 0.34 )	-2.3 ( 0.32 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

144

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0399 ^[53]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

Notes
[53] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

138

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4413 ^[54]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.3

upper limit

0.6

Notes
[54] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

Top of page

End point title

Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

End point description

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: • 28 tender joint count (TJC), • 28 swollen joint count (SJC), • Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; • Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8; Low Disease Activity: > 2.8 and ≤ 10; Moderate Disease Activity: > 10 and ≤ 22; High Disease Activity: > 22. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	159	156	158
Units: units on a scale
least squares mean (standard error)	-2.53 ( 0.889 )	-5.18 ( 0.900 )	-7.81 ( 0.895 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

317

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[55]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-5.27

Confidence interval

level

95%

sides

2-sided

lower limit

-7.73

upper limit

-2.82

Notes
[55] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

315

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0349 ^[56]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-2.65

Confidence interval

level

95%

sides

2-sided

lower limit

-5.11

upper limit

-0.19

Notes
[56] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 24

Top of page

End point title

Change From Baseline in the Disease Activity Score (DAS28) at Week 24

End point description

The DAS28 measures the severity of disease at a specific time and is derived from the following variables: • 28 tender joint count • 28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; • C-reactive protein (CRP) • Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	163	161	161
Units: units on a scale
least squares mean (standard error)	-0.27 ( 0.087 )	-0.57 ( 0.088 )	-0.75 ( 0.087 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[57]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.48

Confidence interval

level

95%

sides

2-sided

lower limit

-0.72

upper limit

-0.24

Notes
[57] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0147 ^[58]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.54

upper limit

-0.06

Notes
[58] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24

Top of page

End point title

Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24

End point description

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. Full analysis set; participants with a baseline value and at least 1 postbaseline value at or prior to Week 24 are included; LOCF imputation was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	161	163	161
Units: units on a scale
least squares mean (standard error)	0.83 ( 0.652 )	2.01 ( 0.651 )	3.27 ( 0.654 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0078 ^[59]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.44

Confidence interval

level

95%

sides

2-sided

lower limit

0.64

upper limit

4.24

Notes
[59] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

324

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1936 ^[60]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.19

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

2.98

Notes
[60] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group, baseline DMARD use, and involvement of >= 3% BSA with psoriasis at baseline as factors and the baseline value as a covariate.

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 16

Top of page

End point title

Percentage of Participants With MASES Improvement ≥ 20% at Week 16

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 16 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	109	97	112
Units: percentage of participants
number (not applicable)	53.2	48.5	54.5

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7585 ^[61]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

-10.9

upper limit

Notes
[61] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5808 ^[62]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-3.9

Confidence interval

level

95%

sides

2-sided

lower limit

-17.4

upper limit

9.7

Notes
[62] - 2-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 16

Top of page

End point title

Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 16

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 16 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	71	71	80
Units: percentage of participants
number (not applicable)	59.2	66.2	71.3

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1303 ^[63]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-3.1

upper limit

Notes
[63] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.361 ^[64]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.3

upper limit

23.2

Notes
[64] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16

Top of page

End point title

Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16

End point description

A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	29.0	40.2	51.5

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[65]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

22.5

Confidence interval

level

95%

sides

2-sided

lower limit

12.4

upper limit

32.6

Notes
[65] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0309 ^[66]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

20.9

Notes
[66] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 24

Top of page

End point title

Percentage of Participants With MASES Improvement ≥ 20% at Week 24

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 24 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. FAS; participants with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who EE at Week 16. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	109	97	112
Units: percentage of participants
number (not applicable)	51.4	51.5	54.5

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5731 ^[67]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.8

Confidence interval

level

95%

sides

2-sided

lower limit

-9.1

upper limit

16.7

Notes
[67] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8876 ^[68]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-12.6

upper limit

14.6

Notes
[68] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 24

Top of page

End point title

Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 24

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 24 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	71	71	80
Units: percentage of participants
number (not applicable)	60.6	67.6	73.8

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1172 ^[69]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

12.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

26.9

Notes
[69] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3695 ^[70]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

7.2

Confidence interval

level

95%

sides

2-sided

lower limit

-8.2

upper limit

22.6

Notes
[70] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With Good or Moderate EULAR Response at Week 24

Top of page

End point title

Percentage of Participants With Good or Moderate EULAR Response at Week 24

End point description

EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	20.1	32.0	42.5

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[71]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

22.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

32.1

Notes
[71] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0123 ^[72]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

11.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.7

upper limit

20.7

Notes
[72] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With a ACR 50 Response at Week 16

Top of page

End point title

Percentage of Participants With a ACR 50 Response at Week 16

End point description

Percentage of participants with an American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	8.3	12.4	15.0

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.052 ^[73]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

13.5

Notes
[73] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2052 ^[74]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

4.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.2

upper limit

10.6

Notes
[74] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With an ACR 70 Response at Week 16

Top of page

End point title

Percentage of Participants With an ACR 70 Response at Week 16

End point description

Percentage of participants with an American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Full analysis set; Participants who discontinued early, or who did not have sufficient data for a definitive determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	2.4	4.7	3.6

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5154 ^[75]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-2.4

upper limit

4.8

Notes
[75] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2527 ^[76]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

2.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

6.2

Notes
[76] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With an ACR 50 Response at Week 24

Top of page

End point title

Percentage of Participants With an ACR 50 Response at Week 24

End point description

Percentage of participants with an American College of Rheumatology 50% (ACR50) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	7.7	13.6	16.2

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.018 ^[77]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

8.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.6

upper limit

15.1

Notes
[77] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0807 ^[78]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

12.3

Notes
[78] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With a ACR 70 Response at Week 24

Top of page

End point title

Percentage of Participants With a ACR 70 Response at Week 24

End point description

Percentage of participants with an American College of Rheumatology 70% (ACR70) response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Full analysis set; Participants who discontinued early, escaped early at Week 16 or who did not have sufficient data for a definitive determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	169	169	167
Units: percentage of participants
number (not applicable)	3.6	4.1	5.4

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.423 ^[79]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

1.8

Confidence interval

level

95%

sides

2-sided

lower limit

-2.6

upper limit

6.2

Notes
[79] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

338

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.787 ^[80]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

4.6

Notes
[80] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 16

Top of page

End point title

Percentage of Participants Achieving a MASES Score of Zero at Week 16

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 16 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 (i.e., pre-existing enthesopathy) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	109	97	112
Units: percentage of participants
number (not applicable)	24.8	19.6	20.5

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4707 ^[81]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-4.1

Confidence interval

level

95%

sides

2-sided

lower limit

-14.8

upper limit

6.5

Notes
[81] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3547 ^[82]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-16.6

upper limit

5.7

Notes
[82] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16

Top of page

End point title

Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 16 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set; participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) are included; LOCF was used. Participants who did not have sufficient data (observed or imputed) for a determination of response status at Week 16 were counted as non-responders.

End point type

Secondary

End point timeframe

Week 16

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	71	71	80
Units: percentage of participants
number (not applicable)	35.2	40.8	41.3

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4175 ^[83]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-8.6

upper limit

21.8

Notes
[83] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.437 ^[84]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.4

Confidence interval

level

95%

sides

2-sided

lower limit

-9.1

upper limit

21.8

Notes
[84] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 24

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End point title

Percentage of Participants Achieving a MASES Score of Zero at Week 24

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 24 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Full analysis set; participants with a baseline MASES > 0 are included; LOCF was used. The Week 16 value was carried over to Week 24 for participants who escaped early at Week 16. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	109	97	112
Units: percentage of participants
number (not applicable)	28.4	20.6	27.7

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

206

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2032 ^[85]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-7.7

Confidence interval

level

95%

sides

2-sided

lower limit

-19.3

upper limit

3.8

Notes
[85] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

221

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9463 ^[86]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-12.1

upper limit

11.3

Notes
[86] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 24

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End point title

Percentage of Participants Achieving a Dactylitis Score of Zero at Week 24

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 24 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Participants who did not have sufficient data for a determination of response status at Week 24 were counted as non-responders.

End point type

Secondary

End point timeframe

Week 24

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	71	71	80
Units: percentage of participants
number (not applicable)	36.6	45.1	46.3

Statistical Analysis 1

Statistical analysis description

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

151

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2321 ^[87]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

-5.8

upper limit

25.4

Notes
[87] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

142

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.252 ^[88]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

9.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.2

upper limit

25.3

Notes
[88] - Two-sided p-value is based on the CMH test adjusting for baseline DMARD use and involvement of >= 3% BSA with psoriasis at baseline.

Secondary: Percentage of Participants With an ACR 20 Response at Week 52

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End point title

Percentage of Participants With an ACR 20 Response at Week 52

End point description

Percentage of participants with an ACR response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm VAS); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (HAQ-DI); ◦ C-Reactive Protein. 2 sided 95% confidence interval (CI) is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population consisted of all participants who were randomized or re-randomized to apremilast at any time during the study; only subjects who had sufficient data for a definitive determination of response at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	54	67	116	127
Units: percentage of participants
number (confidence interval 95%)	59.3 (45.0 to 72.4)	58.2 (45.5 to 70.2)	56.0 (46.5 to 65.2)	63.0 (54.0 to 71.4)

No statistical analyses for this end point

Secondary: Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52

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End point title

Change From Baseline in Health Assessment Questionnaire - Disability Index (HAQ-DI) at Week 52

End point description

The HAQ-DI is a patient-reported questionnaire consisting of 20 questions referring to 8 domains: dressing/grooming, arising, eating, walking, hygiene, reach, grip, and usual activities. Participants assessed their ability to do each task over the past week using the following response categories: without any difficulty (0); with some difficulty (1); with much difficulty (2); and unable to do (3). Scores on each task are summed and averaged to provide an overall score ranging from 0 to 3, where zero represents no disability and three very severe, high-dependency disability. Negative mean changes from Baseline in the overall score indicate improvement in functional ability. Apremilast Subjects as Randomized/Re-randomized (AAR) Population consisted of subjects who were randomized or re-randomized to apremilast at any time during the study. Only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	55	67	122	127
Units: units on a scale
arithmetic mean (standard deviation)	-0.34 ( 0.407 )	-0.34 ( 0.491 )	-0.33 ( 0.505 )	-0.35 ( 0.505 )

No statistical analyses for this end point

Secondary: Change From Baseline in the SF-36 Physical Functioning Scale Score at Week 52

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End point title

Change From Baseline in the SF-36 Physical Functioning Scale Score at Week 52

End point description

The Medical Outcome Study Short Form 36-Item Health Survey, Version 2 (SF-36) is a self-administered instrument that measures the impact of disease on overall quality of life and consists of 36 questions in eight domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). Norm-based scores were used in analyses, calibrated so that 50 is the average score and the standard deviation equals 10. Higher scores indicate a higher level of functioning. The physical functioning domain assesses limitations in physical activities because of health problems. A positive change from Baseline score indicates an improvement. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	55	66	121	127
Units: units on a scale
arithmetic mean (standard deviation)	7.76 ( 8.236 )	6.87 ( 7.241 )	5.68 ( 8.467 )	5.87 ( 8.008 )

No statistical analyses for this end point

Secondary: Percentage of Participants With a Modified PsARC Response at Week 52

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End point title

Percentage of Participants With a Modified PsARC Response at Week 52

End point description

Modified PsARC response is defined as improvement in at least 2 of the 4 measures, at least one of which must be tender joint count or swollen joint count, and no worsening in any of the 4 measures: • 78 tender joint count, • 76 swollen joint count, • Patient global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0 mm = lowest disease activity and 100 mm = highest. Improvement or worsening in joint counts is defined as decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments is defined as decrease or increase, respectively, from baseline by ≥ 20 mm VAS. 2-sided 95% CI is based on the Clopper-Pearson method. Apremilast Subjects as Randomized/Re-randomized (AAR) population; only subjects who had sufficient data for a definitive response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	53	66	116	124
Units: percentage of participants
number (confidence interval 95%)	81.1 (68.0 to 90.6)	75.8 (63.6 to 85.5)	71.6 (62.4 to 79.5)	79.0 (70.8 to 85.8)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 52

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End point title

Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 52

End point description

The percentage of participants with Baseline psoriasis body surface area (BSA) involvement ≥ 3% who achieved 75% or greater improvement from Baseline in Psoriasis Area and Severity Index (PASI) score after 52 weeks. The Psoriasis Area and Severity Index (PASI) score is a combination of the intensity of psoriasis, assessed by erythema (reddening), induration (plaque thickness) and desquamation (scaling) scored on a scale from 0 (none) to 4 (very severe), together with the percentage of the area affected, rated on a scale from 0 (no involvement) to 6 (90% to 100% involvement). PASI scoring is performed at four body areas, the head, arms, trunk, and legs. The total PASI score ranges from 0 to 72. The higher the total score, the more severe the disease. 2-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline Psoriasis Body Surface Area ≥ 3% and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	24	35	63	64
Units: percentage of participants
number (confidence interval 95%)	33.3 (15.6 to 55.3)	28.6 (14.6 to 46.3)	28.6 (17.9 to 41.3)	39.1 (27.1 to 52.1)

No statistical analyses for this end point

Secondary: Change From Baseline in the Patient Assessment of Pain at Week 52

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End point title

Change From Baseline in the Patient Assessment of Pain at Week 52

End point description

The participant was asked to place a vertical line on a 100-mm visual analog scale on which the left-hand boundary (score = 0 mm) represents "no pain," and the right-hand boundary (score = 100 mm) represents "pain as severe as can be imagined." The distance from the mark to the left-hand boundary was recorded in millimeters. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	55	66	122	127
Units: mm
arithmetic mean (standard deviation)	-19.9 ( 24.54 )	-19.1 ( 26.95 )	-14.9 ( 24.86 )	-18.7 ( 27.01 )

No statistical analyses for this end point

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 52

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End point title

Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 52

End point description

The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing enthesopathy) and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	34	48	66	87
Units: units on a scale
arithmetic mean (standard deviation)	-2.5 ( 3.10 )	-2.2 ( 3.01 )	-2.2 ( 2.98 )	-1.9 ( 2.99 )

No statistical analyses for this end point

Secondary: Change From Baseline in the Dactylitis Severity Score at Week 52

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End point title

Change From Baseline in the Dactylitis Severity Score at Week 52

End point description

Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value > 0 (i.e., pre-existing dactylitis) and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	22	26	52	61
Units: units on a scale
arithmetic mean (standard deviation)	-3.1 ( 4.26 )	-3.8 ( 4.52 )	-2.9 ( 3.67 )	-3.6 ( 4.30 )

No statistical analyses for this end point

Secondary: Change From Baseline in the CDAI Score at Week 52

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End point title

Change From Baseline in the CDAI Score at Week 52

End point description

The Clinical Disease Activity Index (CDAI) is a composite index that is calculated as the sum of the: •28 tender joint count (TJC), •28 swollen joint count (SJC), •Patient's Global Assessment of Disease Activity measured on a 10 cm visual analog scale (VAS), where 0 cm = lowest disease activity and 10 cm = highest; •Physician's Global Assessment of Disease Activity -measured on a 10 cm VAS, where 0 cm = lowest disease activity and 10 cm = highest. The CDAI score ranges from 0-76 where lower scores indicate less disease activity. The following thresholds of disease activity have been defined for the CDAI: Remission: ≤ 2.8 Low Disease Activity: > 2.8 and ≤ 10 Moderate Disease Activity: > 10 and ≤ 22 High Disease Activity: > 22. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	53	66	116	124
Units: units on a scale
arithmetic mean (standard deviation)	-13.54 ( 10.689 )	-12.38 ( 10.308 )	-12.86 ( 12.654 )	-14.14 ( 11.354 )

No statistical analyses for this end point

Secondary: Change From Baseline in the DAS28 at Week 52

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End point title

Change From Baseline in the DAS28 at Week 52

End point description

The DAS28 measures the severity of disease at a specific time and is derived from the following variables: •28 tender joint count •28 swollen joint count, which do not include the DIP joints, the hip joint, or the joints below the knee; •C-reactive protein (CRP) •Patient's global assessment of disease activity. DAS28(CRP) scores range from 0 to approximately 10, with the upper bound dependent on the highest possible level of CRP. A DAS28 score higher than 5.1 indicates high disease activity, a DAS28 score less than 3.2 indicates low disease activity, and a DAS28 score less than 2.6 indicates clinical remission. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a Baseline value and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	54	67	121	127
Units: units on a scale
arithmetic mean (standard deviation)	-1.28 ( 1.102 )	-1.29 ( 1.156 )	-1.21 ( 1.063 )	-1.41 ( 1.204 )

No statistical analyses for this end point

Secondary: Change From Baseline in the FACIT-Fatigue Scale Score at Week 52

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End point title

Change From Baseline in the FACIT-Fatigue Scale Score at Week 52

End point description

The FACIT-Fatigue scale is a 13-item self-administered questionnaire that assesses both the physical and functional consequences of fatigue. Each question is answered on a 5-point scale, where 0 means "not at all," and 4 means "very much." The FACIT-Fatigue scale score ranges from 0 to 52, with higher scores denoting lower levels of fatigue. A positive change from baseline score indicates an improvement. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; participants with a baseline value and a Week 52 value are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	54	65	121	127
Units: units on a scale
arithmetic mean (standard deviation)	6.72 ( 8.996 )	5.66 ( 8.738 )	4.78 ( 8.526 )	6.20 ( 8.679 )

No statistical analyses for this end point

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 52

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End point title

Percentage of Participants With MASES Improvement ≥ 20% at Week 52

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 52 weeks. The MASES quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants with a baseline MASES > 0 and who had sufficient data for a definitive response at Week 52.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	34	48	66	87
Units: percentage of participants
number (confidence interval 95%)	73.5 (55.6 to 87.1)	75.0 (60.4 to 86.4)	77.3 (65.3 to 86.7)	71.3 (60.6 to 80.5)

No statistical analyses for this end point

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 52

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End point title

Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 52

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	22	26	52	61
Units: percentage of participants
number (confidence interval 95%)	95.5 (77.2 to 99.9)	92.3 (74.9 to 99.1)	88.5 (76.6 to 95.6)	91.8 (81.9 to 97.3)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving Good or Moderate EULAR Response at Week 52

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End point title

Percentage of Participants Achieving Good or Moderate EULAR Response at Week 52

End point description

A EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on the DAS-28 score. A Good Response is defined as an improvement (decrease) in the DAS28 of more than 1.2 compared with Baseline and attainment of a DAS28 score less than or equal to 3.2. A Moderate Response is defined as either: • an improvement (decrease) in the DAS28 of greater than 0.6 and less than or equal to 1.2 and attainment of a DAS28 score of less than or equal to 5.1 or, • an improvement (decrease) in the DAS28 of more than 1.2 and attainment of a DAS28 score of greater than 3.2. 2-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	54	67	121	127
Units: percentage of participants
number (not applicable)	64.8	73.1	69.4	74.8

No statistical analyses for this end point

Secondary: Percentage of Participants With an ACR 50 Response at Week 52

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End point title

Percentage of Participants With an ACR 50 Response at Week 52

End point description

Percentage of participants with an ACR 50 response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 50% improvement in 78 tender joint count; • ≥ 50% improvement in 76 swollen joint count; and • ≥ 50% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. 2-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	53	66	119	126
Units: percentage of participants
number (confidence interval 95%)	28.3 (16.8 to 42.3)	31.8 (20.9 to 44.4)	25.2 (17.7 to 34.0)	30.2 (22.3 to 39.0)

No statistical analyses for this end point

Secondary: Percentage of Participants With an ACR 70 Response at Week 52

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End point title

Percentage of Participants With an ACR 70 Response at Week 52

End point description

Percentage of participants with an ACR70 response. A participant was a responder if the following 3 criteria for improvement from Baseline were met: • ≥ 70% improvement in 78 tender joint count; • ≥ 70% improvement in 76 swollen joint count; and • ≥ 70% improvement in at least 3 of the 5 following parameters: ◦ Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); ◦ Patient's global assessment of disease activity (measured on a 100 mm VAS); ◦ Physician's global assessment of disease activity (measured on a 100 mm VAS); ◦ Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); ◦ C-Reactive Protein. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; only those participants who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	53	67	120	125
Units: percentage of participants
number (confidence interval 95%)	20.8 (10.8 to 34.1)	14.9 (7.4 to 25.7)	9.2 (4.7 to 15.8)	10.4 (5.7 to 17.1)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 52

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End point title

Percentage of Participants Achieving a MASES Score of Zero at Week 52

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improves to 0 after 24 weeks. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Archilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses. 2-sided 95% confidence interval is based on the Clopper-Pearson method. Apremilast Subjects as Randomized/Re-randomized Population; subjects with a baseline value > 0 and who had sufficient data for a definitive response at Week 52 are included.

End point type

Secondary

End point timeframe

Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	34	48	66	87
Units: percentage of participants
number (confidence interval 95%)	44.1 (27.2 to 62.1)	43.8 (29.5 to 58.8)	33.3 (22.2 to 46.0)	36.8 (26.7 to 47.8)

No statistical analyses for this end point

Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 52

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End point title

Percentage of Participants Achieving a Dactylitis Score of Zero at Week 52

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population; Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and who had sufficient data for a definitive determination of response status at Week 52 are included.

End point type

Secondary

End point timeframe

Week 52

End point values	Placebo /Apremilast 20 mg	Placebo/Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	22	26	52	61
Units: percentage of participants
number (confidence interval 95%)	68.2 (45.1 to 86.1)	80.8 (60.6 to 93.4)	75.0 (61.1 to 86.0)	68.9 (55.7 to 80.1)

No statistical analyses for this end point

Secondary: Number of Participants with Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

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End point title

Number of Participants with Treatment Emergent Adverse Events (TEAEs) During the Placebo-Controlled Phase

End point description

TEAE is an adverse event (AE) with a start date on or after the first dose of IP and no later than 28 days after the last dose; an AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study; a serious AE= an AE that results in death, is life-threatening, requires inpatient hospitalization or prolongation of existing hospitalization, results in persistent or significant disability, is a congenital anomaly or constitutes an important medical event. The investigator assessed severity of an AE by a grading scale: Mild: asymptomatic or with mild symptoms, Moderate-symptoms causing moderate discomfort or Severe- symptoms causing severe discomfort or pain. 1 subject randomized to 30 mg APR who received PBO in error is counted in the PBO group;1 subject randomized to PBO who received 30 mg APR in error is counted in the 30 mg group;1 subject randomized to PBO who received 20 mg APR in error is counted in the 20 mg group

End point type

Secondary

End point timeframe

Week 0 to Week 16 for placebo participants who entered EE at Week 16 and up to Week 24 for all other participants (placebo participants who remained on placebo through week 24 and participants randomized to the APR 20 mg BID or APR 30 mg BID)

End point values	Placebo	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	168	170	167
Units: participants
Any TEAE	83	100	104
Any Drug-Related TEAE	33	50	62
Any Severe TEAE	8	5	10
Any Serious TEAE (SAE)	9	3	6
Any Serious Drug-Related TEAE	2	0	0
Any TEAE Leading to Drug Interruption	4	20	16
Any TEAE Leading to Drug Withdrawal	10	13	12
Any TEAE Leading to Death	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with Treatment Emergent Adverse Events During the Apremilast Exposure Period

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End point title

Number of Participants with Treatment Emergent Adverse Events During the Apremilast Exposure Period

End point description

A TEAE is an adverse event (AE) with a start date on or after the date of the first dose of investigational product (IP) and no later than 28 days after the last dose of IP. An adverse event (AE) is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. A serious AE is any AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. For both AEs and SAEs the investigator assessed the severity of the event according to the grading scale: Mild: asymptomatic or with mild symptoms, Moderate: symptoms causing moderate discomfort or Severe: symptoms causing severe discomfort or pain. Apremilast subjects as treated population.

End point type

Secondary

End point timeframe

Week 0 to Week 260; median duration of exposure to apremilast 20 mg BID was 121.71 weeks and 232.50 weeks for apremilast 30 mg BID

End point values	Apremilast 20 mg (Pre-switch)	Apremilast 20 mg/30 mg (Post-switch)	Apremilast 30 mg
Number of subjects analysed	241	97	242
Units: participants
Any TEAE	194	64	209
Any Drug-Related TEAE	98	11	111
Any Severe TEAE	21	0	30
Any Serious TEAE (SAE)	38	4	54
Any Serious Drug-Related TEAE\|	5	0	3
Any TEAE Leading to Drug Interruption	48	4	53
Any TEAE Leading to Drug Withdrawal	30	0	30
Any TEAE Leading to death	0	1	0

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs are reported for the PBO-controlled phase: Weeks 0 -16 for PBO subjects who entered EE at Week 16 and up to Week 24 for all others; AE's are reported for the APR Exposure Period: Weeks 0 - 260

Adverse event reporting additional description

Median duration: APR 20 mg BID = 121.71 weeks; APR 30 mg BID = 232.50 weeks; 1 subject randomized to 30 mg APR who received PBO in error is counted in the PBO group; 1 subject randomized to PBO who received 30 mg APR in error is counted in the 30 mg group; 1 subject randomized to PBO who received 20 mg APR in error is counted in the 20 mg group

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

V14.0

Reporting group title

Weeks 0-24: Placebo (Placebo-Controlled Phase)

Reporting group description

Participants received placebo tablets twice daily during the placebo-controlled phase. Includes data through Week 16 for participants who escaped early, and through Week 24 for all other participants.

Reporting group title

Weeks 0-24: Apremilast 20 mg (Placebo- Controlled Phase)

Reporting group description

Participants received 20 mg apremilast tablets twice daily during the 24-week placebo-controlled phase.

Reporting group title

Weeks 0-24: Apremilast 30 mg (Placebo- Controlled Phase)

Reporting group description

Participants received 30 mg apremilast tablets PO twice daily during the 24-week placebo-controlled phase.

Reporting group title

APR Exposure Period Up to 5 Years: Apremilast 20 mg

Reporting group description

Participants who received apremilast 20 mg twice daily regardless of when the apremilast exposure started (at Week 0, 16 or 24). Only TEAEs that occurred during apremilast 20 mg BID treatment (before the switch to 30 mg apremilast) were included.

Reporting group title

APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg

Reporting group description

Participants who switched from apremilast 20 mg twice daily to apremilast 30 mg BID. Only the TEAEs that occurred during apremilast 30 mg twice daily treatment were included.

Reporting group title

APR Exposure Period Up to 5 Years: Apremilast 30 mg

Reporting group description

Participants who received apremilast 30 mg twice daily throughout the study regardless of when the apremilast-exposure started (at Week 0, 16, or 24).

Serious adverse events	Weeks 0-24: Placebo (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 20 mg (Placebo- Controlled Phase)	Weeks 0-24: Apremilast 30 mg (Placebo- Controlled Phase)	APR Exposure Period Up to 5 Years: Apremilast 20 mg	APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg	APR Exposure Period Up to 5 Years: Apremilast 30 mg
Total subjects affected by serious adverse events
subjects affected / exposed	9 / 168 (5.36%)	4 / 170 (2.35%)	6 / 167 (3.59%)	38 / 241 (15.77%)	4 / 97 (4.12%)	54 / 242 (22.31%)
number of deaths (all causes)	0	0	0	0	1	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Breast cancer
subjects affected / exposed	0 / 168 (0.00%)	1 / 170 (0.59%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer stage III
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Lipoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Lung adenocarcinoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Oncocytoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Parathyroid tumour benign
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Vascular disorders
Arterial thrombosis limb
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Hypertension
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	2 / 241 (0.83%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	0 / 242 (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
Thrombophlebitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Surgical and medical procedures
Alcohol rehabilitation
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
General disorders and administration site conditions
Chest pain
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Impaired healing
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Non-cardiac chest pain
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Pyrexia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Breast enlargement
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Endometrial hyperplasia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Ovarian haemorrhage
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Uterine haemorrhage
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Respiratory, thoracic and mediastinal disorders
Interstitial lung disease
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nasal polyps
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Nasal septum deviation
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Pulmonary embolism
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	1 / 97 (1.03%)	0 / 242 (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
Tonsillar hypertrophy
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Psychiatric disorders
Anxiety
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	1 / 97 (1.03%)	0 / 242 (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
Mental disorder
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Suicidal ideation
subjects affected / exposed	0 / 168 (0.00%)	1 / 170 (0.59%)	0 / 167 (0.00%)	2 / 241 (0.83%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Investigations
Blood pressure increased
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 168 (0.00%)	1 / 170 (0.59%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 1	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
Cerebral haemorrhage traumatic
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Concussion
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Contusion
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	1 / 167 (0.60%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Head injury
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Meniscus lesion
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Post procedural haemorrhage
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Procedural complication
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Radius fracture
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Snake bite
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Tibia fracture
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Traumatic haematoma
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Ulna fracture
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Whiplash injury
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	1 / 167 (0.60%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	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
Arteriovenous malformation
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Pulmonary arteriovenous fistula
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Angina pectoris
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	2 / 241 (0.83%)	0 / 97 (0.00%)	2 / 242 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	1 / 167 (0.60%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Cardiac failure
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	1 / 97 (1.03%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Myocardial infarction
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Myocardial ischaemia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Sick sinus syndrome
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	1 / 97 (1.03%)	0 / 242 (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
Supraventricular tachycardia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Nervous system disorders
Carpal tunnel syndrome
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Cerebrovascular accident
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Intracranial aneurysm
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	1 / 167 (0.60%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Loss of consciousness
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Migraine
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Polyneuropathy
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Subarachnoid haemorrhage
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Transient ischaemic attack
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Ear and labyrinth disorders
Meniere's disease
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Abdominal hernia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Abdominal pain upper
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Colonic polyp
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal polyp
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	2 / 168 (1.19%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	1 / 2	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
Pancreatitis chronic
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Cholelithiasis
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	1 / 167 (0.60%)	1 / 241 (0.41%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	1 / 1	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
Psoriasis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Urticaria
subjects affected / exposed	1 / 168 (0.60%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	1 / 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
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Calculus urinary
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Endocrine disorders
Acromegaly
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Musculoskeletal and connective tissue disorders
Bursitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Finger deformity
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Intervertebral disc disorder
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Intervertebral disc protrusion
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Lumbar spinal stenosis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	1 / 97 (1.03%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	3 / 241 (1.24%)	0 / 97 (0.00%)	2 / 242 (0.83%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Polyarthritis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Psoriatic arthropathy
subjects affected / exposed	2 / 168 (1.19%)	1 / 170 (0.59%)	1 / 167 (0.60%)	2 / 241 (0.83%)	0 / 97 (0.00%)	7 / 242 (2.89%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 1	0 / 2	0 / 0	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Anal abscess
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Appendicitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Bronchitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Cellulitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis infective
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Chronic sinusitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Erysipelas
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Lobar pneumonia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	1 / 167 (0.60%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	2 / 241 (0.83%)	0 / 97 (0.00%)	1 / 242 (0.41%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rhinitis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Toxic shock syndrome
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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
Urinary tract infection
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Urosepsis
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	1 / 241 (0.41%)	0 / 97 (0.00%)	0 / 242 (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
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	0 / 168 (0.00%)	0 / 170 (0.00%)	0 / 167 (0.00%)	0 / 241 (0.00%)	0 / 97 (0.00%)	1 / 242 (0.41%)
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

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

Non-serious adverse events	Weeks 0-24: Placebo (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 20 mg (Placebo- Controlled Phase)	Weeks 0-24: Apremilast 30 mg (Placebo- Controlled Phase)	APR Exposure Period Up to 5 Years: Apremilast 20 mg	APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg	APR Exposure Period Up to 5 Years: Apremilast 30 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	35 / 168 (20.83%)	66 / 170 (38.82%)	71 / 167 (42.51%)	142 / 241 (58.92%)	36 / 97 (37.11%)	164 / 242 (67.77%)
Vascular disorders
Hypertension
subjects affected / exposed	5 / 168 (2.98%)	3 / 170 (1.76%)	4 / 167 (2.40%)	17 / 241 (7.05%)	3 / 97 (3.09%)	22 / 242 (9.09%)
occurrences all number	6	3	4	20	3	24
Nervous system disorders
Headache
subjects affected / exposed	8 / 168 (4.76%)	16 / 170 (9.41%)	20 / 167 (11.98%)	30 / 241 (12.45%)	4 / 97 (4.12%)	39 / 242 (16.12%)
occurrences all number	10	19	21	142	24	49
General disorders and administration site conditions
Fatigue
subjects affected / exposed	2 / 168 (1.19%)	3 / 170 (1.76%)	8 / 167 (4.79%)	6 / 241 (2.49%)	1 / 97 (1.03%)	16 / 242 (6.61%)
occurrences all number	2	3	8	6	1	17
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 168 (1.79%)	26 / 170 (15.29%)	26 / 167 (15.57%)	40 / 241 (16.60%)	1 / 97 (1.03%)	44 / 242 (18.18%)
occurrences all number	3	29	27	58	1	66
Nausea
subjects affected / exposed	9 / 168 (5.36%)	19 / 170 (11.18%)	23 / 167 (13.77%)	28 / 241 (11.62%)	3 / 97 (3.09%)	47 / 242 (19.42%)
occurrences all number	12	21	26	31	3	59
Vomiting
subjects affected / exposed	1 / 168 (0.60%)	5 / 170 (2.94%)	8 / 167 (4.79%)	10 / 241 (4.15%)	1 / 97 (1.03%)	14 / 242 (5.79%)
occurrences all number	1	6	9	11	1	15
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 168 (0.00%)	4 / 170 (2.35%)	5 / 167 (2.99%)	6 / 241 (2.49%)	1 / 97 (1.03%)	18 / 242 (7.44%)
occurrences all number	0	5	6	8	1	21
Psychiatric disorders
Insomnia
subjects affected / exposed	4 / 168 (2.38%)	1 / 170 (0.59%)	2 / 167 (1.20%)	2 / 241 (0.83%)	0 / 97 (0.00%)	14 / 242 (5.79%)
occurrences all number	4	1	2	2	0	16
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	3 / 168 (1.79%)	2 / 170 (1.18%)	4 / 167 (2.40%)	9 / 241 (3.73%)	0 / 97 (0.00%)	19 / 242 (7.85%)
occurrences all number	3	2	4	10	0	23
Back pain
subjects affected / exposed	3 / 168 (1.79%)	1 / 170 (0.59%)	0 / 167 (0.00%)	12 / 241 (4.98%)	4 / 97 (4.12%)	18 / 242 (7.44%)
occurrences all number	3	1	0	16	4	22
Infections and infestations
Bronchitis
subjects affected / exposed	2 / 168 (1.19%)	3 / 170 (1.76%)	1 / 167 (0.60%)	17 / 241 (7.05%)	3 / 97 (3.09%)	20 / 242 (8.26%)
occurrences all number	2	3	1	26	3	31
Nasopharyngitis
subjects affected / exposed	2 / 168 (1.19%)	7 / 170 (4.12%)	4 / 167 (2.40%)	34 / 241 (14.11%)	12 / 97 (12.37%)	36 / 242 (14.88%)
occurrences all number	2	8	4	61	14	61
Pharyngitis
subjects affected / exposed	1 / 168 (0.60%)	1 / 170 (0.59%)	1 / 167 (0.60%)	14 / 241 (5.81%)	1 / 97 (1.03%)	14 / 242 (5.79%)
occurrences all number	2	1	1	22	1	14
Sinusitis
subjects affected / exposed	3 / 168 (1.79%)	4 / 170 (2.35%)	4 / 167 (2.40%)	12 / 241 (4.98%)	1 / 97 (1.03%)	18 / 242 (7.44%)
occurrences all number	3	4	4	16	1	33
Upper respiratory tract infection
subjects affected / exposed	3 / 168 (1.79%)	11 / 170 (6.47%)	12 / 167 (7.19%)	34 / 241 (14.11%)	6 / 97 (6.19%)	36 / 242 (14.88%)
occurrences all number	3	12	14	65	7	58
Urinary tract infection
subjects affected / exposed	1 / 168 (0.60%)	2 / 170 (1.18%)	5 / 167 (2.99%)	19 / 241 (7.88%)	3 / 97 (3.09%)	22 / 242 (9.09%)
occurrences all number	1	2	5	27	4	41

More information

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Were there any global substantial amendments to the protocol? Yes

24 Jan 2011

1. Modification of protocol language for clarification. 2. Clarified the language around contraception methods to ensure precise description of acceptable methods of contraception given the global nature of Celgene’s trial. In addition, a statement was added into the protocol to ensure that appropriate education regarding contraception methods was provided by the investigator to the subject. 3. Modification to protocol deleting annual chest radiographs allowing local treatment guidelines to dictate when chest radiographs were performed. 4. BSA involved by psoriasis added as study assessment. 5. Alignment of exclusion criteria related to past malignancies across the entire APR Phase 3 program that gave investigators responsibility for determining subject eligibility for previously successfully treated local lesions. 6. Modification of Reasons for Discontinuation to align with what was displayed in the InForm database.

10 Jun 2011

1. Provided correction regarding the Celgene Therapeutic Area Head of the study. 2. Addition of a serum pregnancy test at baseline for FCBP. 3. A clarification in Section 6.2, Contraception Education, which directed the investigator to Section 7.2 of the protocol where the specific details regarding acceptable contraception for this study were found. 4. A clarification in Section 6.6.4, Clinical Laboratory Evaluations, to indicate that a microscopic evaluation was to be performed on all urine samples. 5. Modification to Inclusion Criterion Number 14 – The Female Birth Control Inclusion Criterion was updated to clearly define single or multiple forms of contraception that were acceptable for this study. 6. Addition of a footnote to Inclusion Criterion Number 14 – The Female Birth Control Inclusion Criteria, which clarified that the female subject’s chosen form of contraception must be fully effective by the time the female subject received the first dose of study medication at randomization. 7. Modification to Inclusion Criterion Number 13 – Male Birth Control Inclusion Criteria, which clarified that male subjects must use a “male” latex or non-latex condom. 8. Descriptive text on how to record onset and end dates of SAEs on the SAE Report Form was deleted because it was no longer applicable

20 Apr 2012

1. Provided updates to the contact information for the Medical Monitor of the study. 2. Modification of Section 4.1 Study Design, Section 8.2 Treatment Administration and Schedule, and Section 10.1 Overview regarding site and subject blinding until completion of the 52 Week double-blind phase. 3. Revision of Section 4.1 regarding the replacement of the Safety Review Panel with an independent external DMC. 4. Modification of Section 4.2 Study Design Rationale, Section 9.1 Permitted Concomitant Medications and Procedures, and Section 9.2 Prohibited Concomitant Medications and Procedures to allow the use of topical therapy and/or phototherapy after the Week 52 study visit for worsening skin psoriasis. 5. Addition of a footnote to the Adverse Events row in Table of Events, Section 5, (Tables 1 and 2) which reminded investigators to perform vasculitis assessments and/or psychiatric evaluations as appropriate, when AEs were reported. 6. A revision of the Contraception Education in Section 6.2 and movement of footnote from Section 7.2 to Section 6.2. 7. Addition of Section 6.6.3.1 Vasculitis Assessment providing guidance to investigators. 8. Addition of Section 6.6.3.2 Psychiatric Evaluation to provide guidance to investigators for the management of subjects identified as having thoughts of suicide, attempted suicide, or having a major psychiatric illness. 9. Addition of Section 6.6.3.3 Risk Benefit for Long-term Active Treatment providing guidance to investigators regarding radiographs of symptomatic joints. 10. A change to the open-label IP packaging is described in Sections 6.9.1 and 8.4. 11. A note was added to Section 7.2, Inclusion Criterion 14, to refer investigators to Section 6.2, Contraception Education. 12. AE tables will summarize TEAEs only.12. The term “CRF” (case report form) was changed to “eCRF” globally throughout the document to reflect that data is captured in this study in electronic case report form pages (eCRF).

12 Jul 2012

1. The assessment of the primary efficacy endpoint (ACR 20) was changed to Week 16 instead of Week 24. 2. Assessments of enthesitis and dactylitis (in subjects who present with these manifestations of PsA at baseline) were elevated to be secondary rather than exploratory outcome measures. 3. The secondary endpoints were to be assessed at Week 16, in addition to Weeks 24 and 52. 4. The order of secondary endpoints at Weeks 16, 24 and 52 was modified to coincide with the planned sequence of statistical testing. 5. The modified PsARC and EULAR response were added as secondary efficacy endpoints. 6. The ACR-N was added as an exploratory endpoint. The health-related quality of life endpoints were to be assessed at Week 16, in addition to Weeks 24 and 52. 7. Modification of Section 9.1 Permitted Concomitant Medications to allow use of systemic corticosteroids and DMARDs after the Week 52 study visit for worsening arthritic symptoms of PsA. 8. The statistical approaches for analysis of secondary endpoints were updated. 9. The statistical approaches for subgroup analyses were updated. 10. Citations were included to provide references for the modified PsARC and EULAR response that were added as secondary efficacy outcome measures in this amendment.

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

http://www.ncbi.nlm.nih.gov/pubmed/26792812

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Clinical trials

Clinical Trial Results: A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy and Safety Study of Two Doses of Apremilast (CC-10004) in Subjects with Active Psoriatic Arthritis and a Qualifying Psoriasis Lesion

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 16

Primary: Percentage of Participants With an American College of Rheumatology 20% (ACR20) Response at Week 16

Secondary: Change From Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16

Secondary: Change From Baseline in Health Assessment Questionnaire- Disability Index (HAQ-DI) at Week 16

Secondary: Percentage of Participants With an ACR 20 Response at Week 24

Secondary: Percentage of Participants With an ACR 20 Response at Week 24

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

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

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 16

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 16

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 16

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 16

Secondary: Change from Baseline in Patient’s Assessment of Pain at Week 16

Secondary: Change from Baseline in Patient’s Assessment of Pain at Week 16

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 16

Secondary: Change From Baseline in Dactylitis Severity Score at Week 16

Secondary: Change From Baseline in Dactylitis Severity Score at Week 16

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 16

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 16

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 16

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 16

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 16

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24

Secondary: Change From Baseline in 36-item Short Form Health Survey (SF-36) Physical Functioning Domain at Week 24

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24

Secondary: Percentage of Participants With a Modified Psoriatic Arthritis Response Criteria (PsARC) Response at Week 24

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 24

Secondary: Percentage of Participants Achieving a ≥ 75% Improvement in Psoriasis Area and Severity Index Score (PASI75) at Week 24

Secondary: Change From Baseline in Patient’s Assessment of Pain at Week 24

Secondary: Change From Baseline in Patient’s Assessment of Pain at Week 24

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24

Secondary: Change From Baseline in Maastricht Ankylosing Spondylitis Entheses Score (MASES) at Week 24

Secondary: Change From Baseline in Dactylitis Severity Score at Week 24

Secondary: Change From Baseline in Dactylitis Severity Score at Week 24

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

Secondary: Change From Baseline in Clinical Disease Activity Index (CDAI) at Week 24

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 24

Secondary: Change From Baseline in the Disease Activity Score (DAS28) at Week 24

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24

Secondary: Change From Baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) Score at Week 24

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 16

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 16

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 16

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 16

Secondary: Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16

Secondary: Percentage of Participants With Good or Moderate European League Against Rheumatism (EULAR) Response at Week 16

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 24

Secondary: Percentage of Participants With MASES Improvement ≥ 20% at Week 24

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 24

Secondary: Percentage of Participants With Dactylitis Improvement ≥ 1 Point at Week 24

Secondary: Percentage of Participants With Good or Moderate EULAR Response at Week 24

Secondary: Percentage of Participants With Good or Moderate EULAR Response at Week 24

Secondary: Percentage of Participants With a ACR 50 Response at Week 16

Secondary: Percentage of Participants With a ACR 50 Response at Week 16

Secondary: Percentage of Participants With an ACR 70 Response at Week 16

Secondary: Percentage of Participants With an ACR 70 Response at Week 16

Secondary: Percentage of Participants With an ACR 50 Response at Week 24

Secondary: Percentage of Participants With an ACR 50 Response at Week 24

Secondary: Percentage of Participants With a ACR 70 Response at Week 24

Secondary: Percentage of Participants With a ACR 70 Response at Week 24

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 16

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 16

Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16

Secondary: Percentage of Participants Achieving a Dactylitis Score of Zero at Week 16

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 24

Secondary: Percentage of Participants Achieving a MASES Score of Zero at Week 24

Clinical Trial Results:
A Phase 3, Multicenter, Randomized, Double-blind, Placebo-controlled, Parallel-group, Efficacy and Safety Study of Two Doses of Apremilast (CC-10004) in Subjects with Active Psoriatic Arthritis and a Qualifying Psoriasis Lesion