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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.

Summary
EudraCT number	2010-018386-32
Trial protocol	CZ EE GB BE DE HU ES IT PL BG
Global end of trial date	26 Jan 2017

Results information
Results version number	v1(current)
This version publication date	11 Feb 2018
First version publication date	11 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-003

ISRCTN number

US NCT number

NCT01212757

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, United States, 07901

Public contact

ClinicalTrialDisclosure, Celgene Corporation, 01 888-260-1599, ClinicalTrialDisclosure@celgene.com

Scientific contact

Nikolay Delev, MD, Celgene Corporation, 01 908-897-5662, 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

10 May 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Jan 2017

Was the trial ended prematurely?

Main objective of the trial

The primary objective of this study was to evaluate the clinical efficacy of 2 doses of apremilast (APR) (20 mg or 30 mg orally twice daily [BID]), compared with placebo (PBO), on the signs and symptoms of Psoriatic Arthritis (PsA) after administration for16 weeks.

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

27 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

Belgium: 5

Country: Number of subjects enrolled

Bulgaria: 37

Country: Number of subjects enrolled

Canada: 41

Country: Number of subjects enrolled

Czech Republic: 88

Country: Number of subjects enrolled

Estonia: 66

Country: Number of subjects enrolled

France: 6

Country: Number of subjects enrolled

Germany: 10

Country: Number of subjects enrolled

Hungary: 8

Country: Number of subjects enrolled

Italy: 14

Country: Number of subjects enrolled

Poland: 57

Country: Number of subjects enrolled

Russian Federation: 29

Country: Number of subjects enrolled

South Africa: 18

Country: Number of subjects enrolled

Spain: 13

Country: Number of subjects enrolled

Taiwan: 11

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 75

Worldwide total number of subjects

488

EEA total number of subjects

314

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)

440

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

This study was a multicenter study with 84 sites from the United States, Canada, Europe, Russia, Australia, South Africa and Taiwan.

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

Investigator, Monitor, Data analyst, Subject

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 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 (Wk) 16 were re-randomized to either 20 mg or 30 mg apremilast twice daily [(early escape (EE)].

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 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 30 mg tablets twice daily.

Number of subjects in period 1	Placebo	Apremilast 20 mg	Apremilast 30 mg
Started	162	163	163
Received Treatment	159	163	162
Completed Week 16	148	151	149
Early Escape at Week 16	88 ^[1]	59 ^[2]	64 ^[3]
Completed	143	143	142
Not completed	19	20	21
Consent withdrawn by subject	7	9	3
Adverse event, non-fatal	4	5	12
Miscellaneous	1	2	-
Lost to follow-up	1	1	2
Randomization Error	3	-	1
Lack of efficacy	3	2	2
Protocol deviation	-	1	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 24 - 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

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

Apremilast 30 mg

Arm description

Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 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 in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 20 mg apremilast twice daily during 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 a day.

Placebo / Apremilast 20 mg XO

Arm description

Participants initially randomized to receive placebo twice daily in the 24-week placebo-controlled phase were re-randomized at Week 24 (XO) to receive 20 mg apremilast twice daily during 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 a day.

Placebo / Apremilast 30 mg EE

Arm description

Participants initially randomized to placebo twice daily in the 24-week placebo-controlled phase were re-randomized due to early escape (EE) at Week 16 to receive 30 mg apremilast twice daily during 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 a day

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 during 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 a day.

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	137	134	43	27	41	28
Completed	125	114	35	25	34	28
Not completed	12	20	8	2	7	0
Consent withdrawn by subject	3	7	3	1	3	-
Adverse event, non-fatal	2	3	1	-	2	-
Non-compliance with study drug	-	2	-	-	-	-
Unspecified	1	1	-	-	-	-
Lost to follow-up	1	-	-	1	-	-
Lack of efficacy	5	7	4	-	2	-

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

Participants initially randomized to placebo tablets twice daily in the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 continued receiving apremilast 20 mg BID 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 20 mg tablets twice daily.

Placebo/Apremilast 30 mg

Arm description

Participants initially randomized to placebo tablets BID in the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg BID 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	119	109	58	60
Completed	107	95	48	51
Not completed	12	14	10	9
Consent withdrawn by subject	7	9	4	6
Adverse event, non-fatal	1	1	2	2
Miscellaneous	-	-	-	1
Lost to follow-up	-	2	-	-
Lack of efficacy	4	2	4	-

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

Participants initially randomized to placebo tablets twice daily during the 24-week placebo controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg 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 20 mg tablets twice daily.

Placebo/Apremilast 30 mg

Arm description

Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to apremilast 30 mg tablets BID at Week 16 or Week 24 and continued receiving apremilast 30 mg twice daily 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 4	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	107	95	48	51
Completed	89	84	42	46
Not completed	18	11	6	5
Consent withdrawn by subject	5	1	1	1
Adverse event, non-fatal	4	1	2	-
Miscellaneous	-	3	-	2
Non-compliance with study drug	-	1	-	-
Lost to follow-up	-	-	-	1
Lack of efficacy	8	5	3	1
Protocol deviation	1	-	-	-

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

Participants initially randomized to 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 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

Arm description

Participants initially randomized to placebo tablets twice daily during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg 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 20 mg tablets twice daily

Placebo/Apremilast 30 mg

Arm description

Participants initially randomized to placebo tablets twice daily 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 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 5 ^[6]	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	89	84	41	46
Completed	80	77	37	39
Not completed	9	7	4	7
Adverse event, serious fatal	-	1	-	1
Consent withdrawn by subject	4	2	1	3
Adverse event, non-fatal	1	2	1	1
Miscellaneous	2	-	-	1
Lost to follow-up	-	-	1	-
Lack of efficacy	2	2	1	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 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 BID in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets BID 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 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 BID during the 24-week placebo-controlled phase were re-randomized to 20 mg apremilast at Week 16 or Week 24 and continued receiving apremilast 20 mg 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.

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	Apremilast 20 mg	Apremilast 30 mg	Placebo/Apremilast 20 mg	Placebo/Apremilast 30 mg
Started	80	77	37	39
Completed	72	69	33	37
Not completed	8	8	5	2
Consent withdrawn by subject	3	3	1	1
Adverse event, non-fatal	2	2	2	-
Miscellaneous	1	1	-	-
Non-compliance with study drug	1	-	-	-
Lack of efficacy	1	2	2	1
Joined	0	0	1	0
1 subject not counted in Year 5	-	-	1	-

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 in the 24-week placebo-controlled phase.

Reporting group values	Placebo	Apremilast 20 mg	Apremilast 30 mg	Total
Number of subjects	162	163	163	488
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)	146	149	145	440
From 65-84 years	16	14	18	48
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	51.2 ( 10.97 )	50.9 ( 11.82 )	50.5 ( 11.20 )	-
Gender, Male/Female
Units: Subjects
Female	87	95	95	277
Male	75	68	68	211
Duration of Psoriatic Arthritis
Units: years
arithmetic mean (standard deviation)	7.76 ( 8.254 )	7.83 ( 8.621 )	6.82 ( 7.592 )	-

End points

Top of page

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 in 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

Reporting group title

Placebo / Apremilast 20 mg XO

Reporting group description

Reporting group title

Placebo / Apremilast 30 mg EE

Reporting group description

Reporting group title

Placebo / Apremilast 30 mg XO

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

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 BID 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 BID 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 BID 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 BID 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

Participants 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

Participants who received apremilast 20 mg BID, 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

Participants who switched from apremilast 20 mg BID to apremilast 30 mg BID. 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

Participants who received apremilast 30 mg BID regardless of when their apremilast-exposure started (at Weeks 0, 16, or 24).

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

Percentage of participants with a ACR 20 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. 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	159	163	162
Units: percentage of participants
number (not applicable)	18.9	37.4	32.1

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.006 ^[2]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

13.4

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

22.7

Notes
[1] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% confidence interval (CI) is based on a normal approximation to the weighted average.
[2] - 2-sided p-value is based on the Cochran-Mantel-Haenszel (CMH) test adjusting for baseline disease modifying antirheumatic drug (DMARD) use.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

^[3]

P-value

= 0.0002 ^[4]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

18.7

Confidence interval

level

95%

sides

2-sided

lower limit

9.1

upper limit

28.2

Notes
[3] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[4] - 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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; participants with a baseline value and at least 1 post-baseline value at or prior to Week 16 are included; Last observation carried forward (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	153	159	154
Units: units on a scale
least squares mean (standard error)	-0.053 ( 0.0358 )	-0.157 ( 0.0351 )	-0.193 ( 0.0354 )

Statistical Analysis 1

Statistical analysis description

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.

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0042 ^[5]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.14

Confidence interval

level

95%

sides

2-sided

lower limit

-0.236

upper limit

-0.045

Notes
[5] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

312

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.032 ^[6]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.104

Confidence interval

level

95%

sides

2-sided

lower limit

-0.199

upper limit

-0.009

Notes
[6] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

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

Top of page

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	159	163	162
Units: percentage of participants
number (not applicable)	15.7	31.3	24.7

Statistical Analysis 1

Statistical analysis description

Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 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

321

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0394 ^[8]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

9.2

Confidence interval

level

95%

sides

2-sided

lower limit

0.5

upper limit

17.8

Notes
[7] - 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.
[8] - The 2-sided p-value is based on the CMH 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

322

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0009 ^[10]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

15.7

Confidence interval

level

95%

sides

2-sided

lower limit

6.7

upper limit

24.7

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.
[10] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

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 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 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	153	159	154
Units: units on a scale
least squares mean (standard error)	-0.085 ( 0.0377 )	-0.165 ( 0.0370 )	-0.206 ( 0.0372 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

= 0.0191 ^[12]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.121

Confidence interval

level

95%

sides

2-sided

lower limit

-0.222

upper limit

-0.02

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.
[12] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

312

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.1179 ^[14]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.08

Confidence interval

level

95%

sides

2-sided

lower limit

-0.18

upper limit

0.02

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 analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	153	159	153
Units: units on a scale
least squares mean (standard error)	0.81 ( 0.678 )	2.17 ( 0.664 )	2.91 ( 0.671 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

306

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.0237 ^[16]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.1

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

3.92

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 analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

312

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.1388 ^[18]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.36

Confidence interval

level

95%

sides

2-sided

lower limit

-0.44

upper limit

3.15

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 (ANCOVA) model with treatment group and baseline DMARD use 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	159	163	162
Units: percentage of participants
number (not applicable)	33.3	47.9	48.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

= 0.0065 ^[20]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

14.9

Confidence interval

level

95%

sides

2-sided

lower limit

4.3

upper limit

25.5

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. Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[20] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.0071 ^[22]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

14.7

Confidence interval

level

95%

sides

2-sided

lower limit

4.1

upper limit

25.2

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. Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[22] - 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	151	157	152
Units: mm
least squares mean (standard error)	-7.0 ( 1.93 )	-12.5 ( 1.89 )	-11.9 ( 1.90 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

303

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0648 ^[23]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10

upper limit

0.3

Notes
[23] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

308

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0347 ^[24]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-5.5

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

-0.4

Notes
[24] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

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

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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	100	105	97
Units: units on a scale
least squares mean (standard error)	-1.0 ( 0.29 )	-0.9 ( 0.28 )	-1.4 ( 0.29 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3496 ^[25]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.4

Notes
[25] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8874 ^[26]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

0.8

Notes
[26] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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 will be rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis 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 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	63	75	70
Units: units on a scale
least squares mean (standard error)	-1.1 ( 0.28 )	-0.8 ( 0.26 )	-1.3 ( 0.26 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5438 ^[27]

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
[27] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

= 0.3759 ^[28]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

Notes
[28] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

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

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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	149	155	146
Units: units on a scale
least squares mean (standard error)	-3.30 ( 0.871 )	-7.75 ( 0.851 )	-6.81 ( 0.869 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

295

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0035 ^[29]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.51

Confidence interval

level

95%

sides

2-sided

lower limit

-5.86

upper limit

-1.16

Notes
[29] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

304

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[30]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.45

Confidence interval

level

95%

sides

2-sided

lower limit

-6.76

upper limit

-2.14

Notes
[30] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

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

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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 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	150	156	151
Units: units on a scale
least squares mean (standard error)	-0.27 ( 0.082 )	-0.74 ( 0.080 )	-0.67 ( 0.080 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

301

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004 ^[31]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-0.61

upper limit

-0.18

Notes
[31] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

306

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[32]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

-0.25

Notes
[32] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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. 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 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	153	157	154
Units: units on a scale
least squares mean (standard error)	0.63 ( 0.724 )	0.91 ( 0.712 )	2.75 ( 0.715 )

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7803 ^[33]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-1.65

upper limit

2.2

Notes
[33] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0318 ^[34]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.12

Confidence interval

level

95%

sides

2-sided

lower limit

0.19

upper limit

4.06

Notes
[34] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	153	159	154
Units: units on a scale
least squares mean (standard error)	1.44 ( 0.688 )	2.97 ( 0.673 )	3.30 ( 0.679 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0473 ^[35]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.86

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

3.7

Notes
[35] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

312

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0997 ^[36]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.29

upper limit

3.35

Notes
[36] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	159	163	162
Units: percentage of participants
number (not applicable)	24.5	39.9	32.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

P-value

= 0.1195 ^[38]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

7.8

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

17.5

Notes
[37] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
[38] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

P-value

= 0.0026 ^[40]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

15.5

Confidence interval

level

95%

sides

2-sided

lower limit

5.6

upper limit

25.5

Notes
[39] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights
[40] - 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 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	152	158	153
Units: mm
least squares mean (standard error)	-8.0 ( 1.90 )	-11.5 ( 1.86 )	-9.7 ( 1.88 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

305

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.5067 ^[41]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-6.8

upper limit

3.4

Notes
[41] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1762 ^[42]

Method

ANCOVA

Parameter type

LS mean Difference

Point estimate

-3.5

Confidence interval

level

95%

sides

2-sided

lower limit

-8.5

upper limit

1.6

Notes
[42] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	100	105	98
Units: units on a scale
least squares mean (standard error)	-0.9 ( 0.29 )	-0.9 ( 0.28 )	-1.3 ( 0.29 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2719 ^[43]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.2

upper limit

0.3

Notes
[43] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

205

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9727 ^[44]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.7

Notes
[44] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

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	63	75	71
Units: units on a scale
least squares mean (standard error)	-1.1 ( 0.27 )	-0.9 ( 0.25 )	-1.4 ( 0.26 )

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

= 0.6777 ^[45]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

0.8

Notes
[45] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use as factors, and the baseline value as a covariate.

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

134

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3705 ^[46]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.4

Notes
[46] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	149	155	148
Units: units on a scale
least squares mean (standard error)	-3.21 ( 0.884 )	-7.71 ( 0.864 )	-6.35 ( 0.878 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

297

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0097 ^[47]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-3.14

Confidence interval

level

95%

sides

2-sided

lower limit

-5.52

upper limit

-0.76

Notes
[47] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

304

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[48]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-4.5

Confidence interval

level

95%

sides

2-sided

lower limit

-6.85

upper limit

-2.16

Notes
[48] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	150	157	152
Units: units on a scale
least squares mean (standard error)	-0.27 ( 0.084 )	-0.73 ( 0.082 )	-0.65 ( 0.083 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

302

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011 ^[49]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.38

Confidence interval

level

95%

sides

2-sided

lower limit

-0.6

upper limit

-0.15

Notes
[49] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[50]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

-0.23

Notes
[50] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	153	157	154
Units: units on a scale
least squares mean (standard error)	0.52 ( 0.721 )	0.68 ( 0.710 )	2.65 ( 0.713 )

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

307

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0303 ^[51]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

4.07

Notes
[51] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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

310

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.8704 ^[52]

Method

ANCOVA

Parameter type

LS mean Difference

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-1.76

upper limit

2.08

Notes
[52] - Based on an analysis of covariance (ANCOVA) model with treatment group and baseline DMARD use 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	104	107	101
Units: percentage of participants
number (not applicable)	52.9	54.2	56.4

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

P-value

= 0.8462 ^[54]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-12.1

upper limit

14.7

Notes
[53] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
[54] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

P-value

= 0.6022 ^[56]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.6

Confidence interval

level

95%

sides

2-sided

lower limit

-9.9

upper limit

17.2

Notes
[55] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights.
[56] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

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 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	66	77	73
Units: percentage of participants
number (not applicable)	59.1	62.3	61.6

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

P-value

= 0.7337 ^[58]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-13.3

upper limit

18.9

Notes
[57] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[58] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

P-value

= 0.6881 ^[60]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-12.7

upper limit

19.3

Notes
[59] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[60] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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	159	163	162
Units: percentage of participants
number (not applicable)	31.4	53.4	48.8

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

P-value

= 0.0014 ^[62]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

17.5

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

27.9

Notes
[61] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[62] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[63]

P-value

= 0.0001 ^[64]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

22.1

Confidence interval

level

95%

sides

2-sided

lower limit

11.7

upper limit

32.5

Notes
[63] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[64] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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 MASES 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	104	107	101
Units: percentage of participants
number (not applicable)	51.0	57.0	57.4

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[65]

P-value

= 0.3376 ^[66]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.6

Confidence interval

level

95%

sides

2-sided

lower limit

-6.8

upper limit

Notes
[65] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[66] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

superiority ^[67]

P-value

= 0.3756 ^[68]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

19.4

Notes
[67] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[68] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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 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	66	77	73
Units: percentage of participants
number (not applicable)	62.1	68.8	68.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

P-value

= 0.3959 ^[70]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-8.7

upper limit

22.2

Notes
[69] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[70] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority ^[71]

P-value

= 0.3941 ^[72]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

-8.7

upper limit

22.4

Notes
[71] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the Cochran-Mantel-Haenszel (CMH) weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[72] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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	159	163	162
Units: percentage of participants
number (not applicable)	21.4	41.7	33.3

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[73]

P-value

= 0.0001 ^[74]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

20.5

Confidence interval

level

95%

sides

2-sided

lower limit

10.8

upper limit

30.3

Notes
[73] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[74] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[75]

P-value

= 0.0142 ^[76]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

12.1

Confidence interval

level

95%

sides

2-sided

lower limit

2.6

upper limit

21.7

Notes
[75] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[76] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o 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	159	163	162
Units: percentage of participants
number (not applicable)	5.0	14.7	10.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[77]

P-value

= 0.0589 ^[78]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.6

Confidence interval

level

95%

sides

2-sided

lower limit

-0.2

upper limit

11.3

Notes
[77] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[78] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[79]

P-value

= 0.0034 ^[80]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.4

upper limit

16.1

Notes
[79] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[80] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o 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	159	163	162
Units: percentage of participants
number (not applicable)	0.6	3.7	1.2

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[81]

P-value

= 0.562 ^[82]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

2.7

Notes
[81] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[82] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[83]

P-value

= 0.057 ^[84]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

upper limit

6.2

Notes
[83] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[84] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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: o Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); o Patient's global assessment of disease activity (measured on a 100 mm VAS); o Physician's global assessment of disease activity (measured on a 100 mm VAS); o Patient's self-assessment of physical function (Health Assessment Questionnaire - Disability Index (HAQ-DI)); o 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	159	163	162
Units: percentage of participants
number (not applicable)	8.8	14.1	11.7

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[85]

P-value

= 0.3629 ^[86]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.1

Confidence interval

level

95%

sides

2-sided

lower limit

-3.5

upper limit

9.6

Notes
[85] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[86] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[87]

P-value

= 0.1323 ^[88]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.4

Confidence interval

level

95%

sides

2-sided

lower limit

-1.5

upper limit

12.3

Notes
[87] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[88] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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	159	163	162
Units: percentage of participants
number (not applicable)	3.1	5.5	2.5

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

322

Analysis specification

Pre-specified

Analysis type

superiority ^[89]

P-value

= 0.2929 ^[90]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

2.4

Confidence interval

level

95%

sides

2-sided

lower limit

-2

upper limit

6.8

Notes
[89] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[90] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

321

Analysis specification

Pre-specified

Analysis type

superiority ^[91]

P-value

= 0.7273 ^[92]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-4.3

upper limit

Notes
[91] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[92] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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	104	107	101
Units: percentage of participants
number (not applicable)	23.1	29.0	20.8

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[93]

P-value

= 0.7023 ^[94]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-13.5

upper limit

9.1

Notes
[93] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[94] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

superiority ^[95]

P-value

= 0.3305 ^[96]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-5.9

upper limit

17.7

Notes
[95] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[96] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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 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	66	77	73
Units: percentage of participants
number (not applicable)	40.9	42.9	41.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

139

Analysis specification

Pre-specified

Analysis type

superiority ^[97]

P-value

= 0.9698 ^[98]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-16

upper limit

16.6

Notes
[97] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[98] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

143

Analysis specification

Pre-specified

Analysis type

superiority ^[99]

P-value

= 0.8205 ^[100]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-14.3

upper limit

18.1

Notes
[99] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[100] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

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

Top of page

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	104	107	101
Units: percentage of participants
number (not applicable)	24.0	29.9	22.8

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

205

Analysis specification

Pre-specified

Analysis type

superiority ^[101]

P-value

= 0.8424 ^[102]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

-1.2

Confidence interval

level

95%

sides

2-sided

lower limit

-12.7

upper limit

10.3

Notes
[101] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[102] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

211

Analysis specification

Pre-specified

Analysis type

superiority ^[103]

P-value

= 0.3395 ^[104]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-6

upper limit

17.8

Notes
[103] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[104] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use

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

Top of page

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 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 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	68	59	68
Units: percentage of participants
number (not applicable)	40.9	44.2	46.6

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30 mg

Number of subjects included in analysis

136

Analysis specification

Pre-specified

Analysis type

superiority ^[105]

P-value

= 0.4811 ^[106]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

5.9

Confidence interval

level

95%

sides

2-sided

lower limit

-10.3

upper limit

22.1

Notes
[105] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[106] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 20 mg

Number of subjects included in analysis

127

Analysis specification

Pre-specified

Analysis type

superiority ^[107]

P-value

= 0.6965 ^[108]

Method

Cochran-Mantel-Haenszel

Parameter type

Adjusted Difference

Point estimate

3.3

Confidence interval

level

95%

sides

2-sided

lower limit

-13.3

upper limit

19.5

Notes
[107] - Adjusted difference is the weighted average of the treatment differences across the 2 strata of baseline DMARD use with the CMH weights. The 2-sided 95% CI is based on a normal approximation to the weighted average.
[108] - The 2-sided p-value is based on the CMH test adjusting for baseline DMARD use.

Secondary: Percentage of Participants with a ACR 20 Response at Week 52

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End point title

Percentage of Participants with a ACR 20 Response at Week 52

End point description

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; ◦C-Reactive Protein. Two-sided 95% confidence interval is based on the Clopper-Pearson method. The Apremilast Subjects as Randomized/Re-randomized (AAR) Population consists of all participants who were randomized or re-randomized to apremilast at any time during the study; only those 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	60	61	121	116
Units: percentage of participants
number (confidence interval 95%)	53.3 (40.0 to 63.3)	47.5 (34.6 to 60.7)	52.9 (43.6 to 62.0)	52.6 (43.1 to 61.9)

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 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. Apremilast Subjects as Randomized/Re-randomized (AAR) Population consisted of subjetcs 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	60	63	125	117
Units: units on a scale
arithmetic mean (standard deviation)	-0.208 ( 0.4831 )	-0.310 ( 0.5990 )	-0.192 ( 0.5729 )	-0.330 ( 0.5089 )

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	60	63	124	115
Units: units on a scale
arithmetic mean (standard deviation)	4.13 ( 9.106 )	5.97 ( 9.612 )	4.05 ( 8.752 )	4.97 ( 9.656 )

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 = a decrease or increase, respectively, from baseline by ≥ 30%, and improvement or worsening in global assessments = a decrease or increase, from baseline by ≥ 20 mm VAS. 2 sided 95% confidence interval 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	60	60	123	114
Units: percentage of participants
number (confidence interval 95%)	78.3 (65.8 to 87.9)	73.3 (60.3 to 83.9)	72.4 (63.6 to 80.0)	74.6 (65.6 to 82.3)

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	60	62	125	117
Units: mm
arithmetic mean (standard deviation)	-15.6 ( 23.77 )	-16.0 ( 24.48 )	-13.5 ( 27.78 )	-12.9 ( 26.54 )

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	40	39	80	78
Units: units on a scale
arithmetic mean (standard deviation)	-2.5 ( 4.41 )	-2.5 ( 2.73 )	-1.7 ( 3.12 )	-2.1 ( 2.82 )

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 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	23	27	57	60
Units: units on a scale
arithmetic mean (standard deviation)	-1.9 ( 1.14 )	-2.1 ( 2.32 )	-1.8 ( 1.98 )	-1.8 ( 2.06 )

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	60	60	123	114
Units: units on a scale
arithmetic mean (standard deviation)	-13.66 ( 9.811 )	-13.13 ( 13.148 )	-12.03 ( 10.492 )	-14.38 ( 11.531 )

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	60	62	125	117
Units: units on a scale
arithmetic mean (standard deviation)	-1.18 ( 1.015 )	-1.18 ( 1.366 )	-1.11 ( 1.059 )	-1.30 ( 1.033 )

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	59	63	123	115
Units: units on a scale
arithmetic mean (standard deviation)	1.97 ( 8.544 )	4.95 ( 9.414 )	2.45 ( 9.481 )	4.38 ( 9.847 )

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 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. 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	40	39	80	78
Units: percentage of participants
number (confidence interval 95%)	72.5 (56.1 to 85.4)	79.5 (63.5 to 90.7)	70.0 (58.7 to 79.7)	69.2 (57.8 to 79.2)

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 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	23	27	57	60
Units: percentage of participants
number (confidence interval 95%)	95.7 (78.1 to 99.9)	88.9 (70.8 to 97.6)	80.7 (68.1 to 90.0)	85.0 (73.4 to 92.9)

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. 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	60	62	125	117
Units: percentage of participants
number (not applicable)	70.0	64.5	68.0	67.5

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 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. 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	59	62	120	118
Units: percentage of participants
number (confidence interval 95%)	30.5 (19.2 to 43.9)	27.4 (16.9 to 40.2)	26.7 (19.0 to 35.5)	18.6 (12.1 to 26.9)

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 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. 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	59	63	123	118
Units: percentage of participants
number (confidence interval 95%)	16.9 (8.4 to 29.0)	14.3 (6.7 to 25.4)	9.8 (5.1 to 16.4)	6.8 (3.0 to 12.9)

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. Two-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	40	39	80	78
Units: percentage of participants
number (confidence interval 95%)	42.5 (27.0 to 59.1)	41.0 (25.6 to 57.9)	40.0 (29.2 to 51.6)	37.2 (26.5 to 48.9)

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 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	23	27	57	60
Units: percentage of participants
number (confidence interval 95%)	78.3 (56.3 to 92.5)	77.8 (57.7 to 91.4)	57.9 (44.1 to 70.9)	65.0 (51.6 to 76.9)

No statistical analyses for this end point

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

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End point title

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

End point description

A Treatment Emergent Adverse Event (TEAE) is an AE with a start date on or after the date of the first dose of Investigational Product (IP). The severity of each adverse event (AE) and serious AE (SAE) was assessed by the investigator and graded based on a scale from Mild to Severe AEs. A serious adverse event (SAE) is any AE which: • Resulted in death • Was life-threatening • Required inpatient hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability/incapacity • Was a congenital anomaly/birth defect • Constituted an important medical event; Safety population included all participants who were randomized and received at least one dose of IP.

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	159	163	162
Units: Participants
Any TEAE\|	72	106	96
Any Drug-Related TEAE\|	28	53	57
Any Severe TEAE\|	5	3	11
Any Serious TEAE (SAE)\|	3	6	4
Any Drug-Related SAE\|	0	3	1
Any TEAE Leading to Drug Interruption\|	11	16	31
Any TEAE Leading to Drug Withdrawal\|	3	5	12
Any TEAE Leading to Death\|	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with TEAEs During the Apremilast-Exposure Period

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End point title

Number of Participants with TEAEs During the Apremilast-Exposure Period

End point description

A Treatment Emergent Adverse Event (TEAE) is an AE with a start date on or after the date of the first dose of Investigational Product (IP). The severity of each adverse event (AE) and serious AE (SAE) was assessed by the investigator and graded based on a scale from Mild to Severe AEs. A serious adverse event (SAE) is any AE which: • Resulted in death • Was life-threatening • Required inpatient hospitalization or prolongation of existing hospitalization • Resulted in persistent or significant disability/incapacity • Was a congenital anomaly/birth defect • Constituted an important medical event; apremilast subjects as treated who received at least 1 dose of apremilast at any time during the study.

End point type

Secondary

End point timeframe

Week 0-260; overall median duration of exposure for APR 20 mg and 30 mg was 198 weeks

End point values	Apremilast 20 mg (Pre-switch)	Apremilast 20 mg/30 mg (Post-switch)	Apremilast 30 mg
Number of subjects analysed	234	113	234
Units: participants
Any TEAE\|	202	53	207
Any Drug-related TEAE\|	102	5	100
Any Severe TEAE\|	35	2	37
Any Serious TEAE\|	41	5	41
Any Serious Drug-related TEAE\|	6	1	6
Any TEAE Leading to Drug Interruption\|	47	4	65
Any TEAE Leading to Drug Withdrawal\|	24	3	30
Any TEAE Leading to Death\|	0	0	2

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

AEs are reported for the placebo-controlled phase from Week 0 - Week 16 for subjects who entered EE at Week 16 and up to Week 24 for all other subjects. AEs are reported for the apremilast exposure period from Week 0 to Week 260.

Adverse event reporting additional description

Overall median exposure to apremilast was 198 weeks.

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 PO BID 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 BID during the 24-week placebo-controlled phase.

Reporting group title

Apremilast 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

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

Reporting group description

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

Reporting group title

Apremilst Exposure 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 Weeks 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)	Apremilast Exposure Period Up to 5 Years: Apremilast 20 mg	Apremilast Exposure Up to 5 Years: Apremilast 20/30 mg	Apremilst Exposure up to 5 Years: Apremilast 30 mg
Total subjects affected by serious adverse events
subjects affected / exposed	3 / 159 (1.89%)	6 / 163 (3.68%)	4 / 162 (2.47%)	41 / 234 (17.52%)	5 / 113 (4.42%)	41 / 234 (17.52%)
number of deaths (all causes)	0	0	0	0	0	2
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Basal cell carcinoma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Benign neoplasm of thyroid gland
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Benign renal neoplasm
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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 metastatic
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Colon adenoma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Colon cancer stage 0
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Endometrial cancer
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	1 / 113 (0.88%)	0 / 234 (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 / 0	0 / 0
Prostatic adenoma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Renal cancer
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	1 / 113 (0.88%)	0 / 234 (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
Renal cell carcinoma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
T-cell lymphoma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Tonsil cancer
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Aortic aneurysm
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Arterial thrombosis limb
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (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
Deep vein thrombosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Hypertension
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	1 / 234 (0.43%)	0 / 113 (0.00%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	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
Peripheral ischaemia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Peripheral vascular disorder
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Subclavian artery stenosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Pyrexia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Hypersensitivity
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Menometrorrhagia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Ovarian cyst
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Pelvic floor muscle weakness
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	1 / 113 (0.88%)	0 / 234 (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
Uterine haemorrhage
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 polyp
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Uterine prolapse
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Vaginal haemorrhage
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Nasal turbinate hypertrophy
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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 fibrosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Depression
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	3 / 234 (1.28%)	0 / 113 (0.00%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 3	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Schizoaffective disorder
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Ankle fracture
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Dislocation of vertebra
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Foreign body
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Graft haemorrhage
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Head injury
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Limb injury
subjects affected / exposed	1 / 159 (0.63%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	0 / 234 (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
Tendon injury
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Vascular pseudoaneurysm
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 disorders
Acute myocardial infarction
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (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
Angina unstable
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Atrial tachycardia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 arrest
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Hypertensive heart disease
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Myocardial ischaemia
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Brain stem stroke
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Carotid artery disease
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Cerebral infarction
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	2 / 234 (0.85%)
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 / 1
Cerebrovascular accident
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 1
Diabetic neuropathy
subjects affected / exposed	1 / 159 (0.63%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	0 / 234 (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
Headache
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Tension headache
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Transient ischaemic attack
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	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
Gastrointestinal disorders
Abdominal adhesions
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Colitis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Diarrhoea
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Gastric volvulus
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Gastritis
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Hernial eventration
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Hiatus hernia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Inguinal hernia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Inguinal hernia, obstructive
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Intestinal obstruction
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Intestinal perforation
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Oesophagitis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Pancreatitis acute
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Small intestinal obstruction
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Cholelithiasis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	2 / 234 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis acute
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Skin and subcutaneous tissue disorders
Hyperhidrosis
subjects affected / exposed	0 / 159 (0.00%)	1 / 163 (0.61%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	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
Lichen planus
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Psoriasis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Renal failure acute
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Renal tubular necrosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Urethral stenosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Goitre
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Acquired claw toe
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Bunion
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Foot deformity
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	0 / 234 (0.00%)	0 / 113 (0.00%)	2 / 234 (0.85%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 159 (0.63%)	0 / 163 (0.00%)	0 / 162 (0.00%)	3 / 234 (1.28%)	0 / 113 (0.00%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 7	0 / 0	0 / 0
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Osteoarthritis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	1 / 113 (0.88%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 4	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Pain in extremity
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Psoriatic arthropathy
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	3 / 234 (1.28%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess soft tissue
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	1 / 113 (0.88%)	0 / 234 (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
Arthritis infective
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Diverticulitis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	1 / 234 (0.43%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	1 / 113 (0.88%)	0 / 234 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal bacterial infection
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Lobar pneumonia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Neuroborreliosis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Oral candidiasis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Peritoneal abscess
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Pneumonia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Scrotal abscess
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Sepsis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Septic shock
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	0 / 234 (0.00%)	0 / 113 (0.00%)	1 / 234 (0.43%)
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
Skin candida
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Urinary tract infection bacterial
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	1 / 234 (0.43%)	0 / 113 (0.00%)	0 / 234 (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
Hyponatraemia
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	0 / 162 (0.00%)	2 / 234 (0.85%)	0 / 113 (0.00%)	0 / 234 (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

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)	Apremilast Exposure Period Up to 5 Years: Apremilast 20 mg	Apremilast Exposure Up to 5 Years: Apremilast 20/30 mg	Apremilst Exposure up to 5 Years: Apremilast 30 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	38 / 159 (23.90%)	73 / 163 (44.79%)	82 / 162 (50.62%)	154 / 234 (65.81%)	19 / 113 (16.81%)	166 / 234 (70.94%)
Vascular disorders
Hypertension
subjects affected / exposed	7 / 159 (4.40%)	4 / 163 (2.45%)	5 / 162 (3.09%)	21 / 234 (8.97%)	4 / 113 (3.54%)	22 / 234 (9.40%)
occurrences all number	7	4	5	21	5	26
Nervous system disorders
Headache
subjects affected / exposed	7 / 159 (4.40%)	9 / 163 (5.52%)	18 / 162 (11.11%)	23 / 234 (9.83%)	0 / 113 (0.00%)	29 / 234 (12.39%)
occurrences all number	8	11	18	28	0	31
Gastrointestinal disorders
Abdominal pain
subjects affected / exposed	1 / 159 (0.63%)	4 / 163 (2.45%)	2 / 162 (1.23%)	14 / 234 (5.98%)	0 / 113 (0.00%)	9 / 234 (3.85%)
occurrences all number	1	6	2	17	0	12
Abdominal pain upper
subjects affected / exposed	0 / 159 (0.00%)	4 / 163 (2.45%)	5 / 162 (3.09%)	11 / 234 (4.70%)	1 / 113 (0.88%)	13 / 234 (5.56%)
occurrences all number	0	5	5	17	1	13
Diarrhoea
subjects affected / exposed	8 / 159 (5.03%)	18 / 163 (11.04%)	25 / 162 (15.43%)	33 / 234 (14.10%)	0 / 113 (0.00%)	40 / 234 (17.09%)
occurrences all number	9	24	30	47	0	55
Dyspepsia
subjects affected / exposed	1 / 159 (0.63%)	4 / 163 (2.45%)	5 / 162 (3.09%)	12 / 234 (5.13%)	0 / 113 (0.00%)	12 / 234 (5.13%)
occurrences all number	1	4	5	13	0	13
Nausea
subjects affected / exposed	3 / 159 (1.89%)	15 / 163 (9.20%)	26 / 162 (16.05%)	25 / 234 (10.68%)	1 / 113 (0.88%)	37 / 234 (15.81%)
occurrences all number	3	18	28	31	1	40
Vomiting
subjects affected / exposed	2 / 159 (1.26%)	5 / 163 (3.07%)	6 / 162 (3.70%)	10 / 234 (4.27%)	1 / 113 (0.88%)	12 / 234 (5.13%)
occurrences all number	2	6	7	11	1	17
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	0 / 159 (0.00%)	4 / 163 (2.45%)	3 / 162 (1.85%)	12 / 234 (5.13%)	0 / 113 (0.00%)	15 / 234 (6.41%)
occurrences all number	0	4	3	15	0	19
Psychiatric disorders
Depression
subjects affected / exposed	2 / 159 (1.26%)	1 / 163 (0.61%)	0 / 162 (0.00%)	13 / 234 (5.56%)	0 / 113 (0.00%)	7 / 234 (2.99%)
occurrences all number	2	1	0	14	0	10
Insomnia
subjects affected / exposed	0 / 159 (0.00%)	3 / 163 (1.84%)	1 / 162 (0.62%)	14 / 234 (5.98%)	0 / 113 (0.00%)	12 / 234 (5.13%)
occurrences all number	0	3	1	14	0	15
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 159 (0.00%)	5 / 163 (3.07%)	3 / 162 (1.85%)	22 / 234 (9.40%)	0 / 113 (0.00%)	14 / 234 (5.98%)
occurrences all number	0	5	5	25	0	19
Osteoarthritis
subjects affected / exposed	0 / 159 (0.00%)	0 / 163 (0.00%)	1 / 162 (0.62%)	11 / 234 (4.70%)	2 / 113 (1.77%)	12 / 234 (5.13%)
occurrences all number	0	0	1	12	2	13
Infections and infestations
Bronchitis
subjects affected / exposed	0 / 159 (0.00%)	5 / 163 (3.07%)	6 / 162 (3.70%)	19 / 234 (8.12%)	1 / 113 (0.88%)	30 / 234 (12.82%)
occurrences all number	0	5	6	34	1	40
Influenza
subjects affected / exposed	0 / 159 (0.00%)	4 / 163 (2.45%)	3 / 162 (1.85%)	13 / 234 (5.56%)	0 / 113 (0.00%)	10 / 234 (4.27%)
occurrences all number	0	6	3	20	0	12
Nasopharyngitis
subjects affected / exposed	6 / 159 (3.77%)	9 / 163 (5.52%)	9 / 162 (5.56%)	28 / 234 (11.97%)	4 / 113 (3.54%)	30 / 234 (12.82%)
occurrences all number	6	9	10	40	4	49
Pharyngitis
subjects affected / exposed	2 / 159 (1.26%)	1 / 163 (0.61%)	2 / 162 (1.23%)	8 / 234 (3.42%)	1 / 113 (0.88%)	15 / 234 (6.41%)
occurrences all number	3	1	2	10	1	19
Rhinitis
subjects affected / exposed	1 / 159 (0.63%)	1 / 163 (0.61%)	1 / 162 (0.62%)	5 / 234 (2.14%)	0 / 113 (0.00%)	13 / 234 (5.56%)
occurrences all number	1	1	1	8	0	14
Sinusitis
subjects affected / exposed	4 / 159 (2.52%)	4 / 163 (2.45%)	3 / 162 (1.85%)	17 / 234 (7.26%)	1 / 113 (0.88%)	15 / 234 (6.41%)
occurrences all number	5	4	3	26	1	18
Upper respiratory tract infection
subjects affected / exposed	6 / 159 (3.77%)	14 / 163 (8.59%)	11 / 162 (6.79%)	42 / 234 (17.95%)	4 / 113 (3.54%)	37 / 234 (15.81%)
occurrences all number	6	18	11	73	7	69
Urinary tract infection
subjects affected / exposed	2 / 159 (1.26%)	3 / 163 (1.84%)	1 / 162 (0.62%)	18 / 234 (7.69%)	4 / 113 (3.54%)	13 / 234 (5.56%)
occurrences all number	2	3	1	24	4	17
Metabolism and nutrition disorders
Hypercholesterolaemia
subjects affected / exposed	1 / 159 (0.63%)	1 / 163 (0.61%)	0 / 162 (0.00%)	14 / 234 (5.98%)	0 / 113 (0.00%)	7 / 234 (2.99%)
occurrences all number	2	1	0	14	0	8

More information

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Were there any global substantial amendments to the protocol? Yes

26 Jan 2011

1. Modification of protocol language for clarification. 2. Clarification of the language around contraception methods to ensure precise description of acceptable methods of contraception given the global nature of Celgene’s trials. 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 SRP 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. 13. 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).

03 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. 7. The health-related quality of life endpoints were to be assessed at Week 16, in addition to Weeks 24 and 52. 8. 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 9. The statistical approaches for analysis of secondary endpoints were updated. 10. The statistical approaches for subgroup analyses were updated. 11. 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/27422893

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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.

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: 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: 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

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

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

Secondary: Percentage of Participants with a ACR 20 Response at Week 52

Secondary: Percentage of Participants with a ACR 20 Response at Week 52

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.