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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 Who Have Not Been Previously Treated with Disease-modifying Antirheumatic Drugs

Summary
EudraCT number	2010-020324-22
Trial protocol	GB HU BE CZ LT IT PL BG EE
Global end of trial date	26 Sep 2017

Results information
Results version number	v1(current)
This version publication date	12 Oct 2018
First version publication date	12 Oct 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-005

ISRCTN number

US NCT number

NCT01307423

WHO universal trial number (UTN)

Sponsor organisation name

Celgene Corporation

Sponsor organisation address

86 Morris Avenue, Summit, NJ, United States, 07901

Public contact

ClinicalTrialDisclosure, Celgene Corporation, +1 8882601599, ClinicalTrialDisclosure@celgene.com

Scientific contact

Nikolay Delev, MD, Celgene Corporation, +1 908-897-5662, 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

17 Oct 2017

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

26 Sep 2017

Was the trial ended prematurely?

Main objective of the trial

To evaluate the clinical efficacy of 2 doses of apremilast (20 mg or 30 mg orally twice per day [BID]), compared with placebo, on the signs and symptoms of psoriatic arthritis (PsA) after 16 weeks’ administration

Protection of trial subjects

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

09 Dec 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

Bulgaria: 41

Country: Number of subjects enrolled

Australia: 12

Country: Number of subjects enrolled

Canada: 47

Country: Number of subjects enrolled

Czech Republic: 30

Country: Number of subjects enrolled

Estonia: 25

Country: Number of subjects enrolled

France: 1

Country: Number of subjects enrolled

Hungary: 27

Country: Number of subjects enrolled

Italy: 10

Country: Number of subjects enrolled

Lithuania: 17

Country: Number of subjects enrolled

New Zealand: 13

Country: Number of subjects enrolled

Poland: 74

Country: Number of subjects enrolled

Romania: 3

Country: Number of subjects enrolled

Russian Federation: 109

Country: Number of subjects enrolled

United Kingdom: 10

Country: Number of subjects enrolled

United States: 108

Worldwide total number of subjects

527

EEA total number of subjects

238

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)

109

From 65 to 84 years

418

85 years and over

Subject disposition

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Recruitment details

The study was conducted in 16 countries including the United States, Canada, Europe, New Zealand, Australia and Russia.

Screening details

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

Period 1 title

Placebo-controlled Phase (Week 0 - 24)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

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

Are arms mutually exclusive

Yes

Placebo

Arm description

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

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants initially randomized to receive placebo tablets twice daily (BID) in the 24-week placebo- controlled phase.

Apremilast 20mg

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

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

Apremilast 30mg

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

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

Number of subjects in period 1	Placebo	Apremilast 20mg	Apremilast 30mg
Started	176	175	176
Received Treatment	176	175	175
Completed Week 16	166	168	166
Early Escape at Week 16	103 ^[1]	73 ^[2]	79 ^[3]
Completed	156	160	155
Not completed	20	15	21
Consent withdrawn by subject	8	4	10
Non-compliance with Study Drug	-	1	1
Adverse event, non-fatal	4	4	6
Unspecified	1	2	-
Lost to follow-up	5	1	2
Lack of efficacy	1	3	2
Protocol deviation	1	-	-

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

Period 2 title

Active Treatment Phase (Week 25-52)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst

Blinding implementation details

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

Apremilast 20mg

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 30mg

Arm description

Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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

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

Placebo/ 20mg Apremilast EE

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Placebo / Apremilast 20 mg XO

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Placebo / Apremilast 30 mg EE

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Placebo / Apremilast 30 mg XO

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Participants initially randomized to receive placebo twice daily were re-randomized at Week 24 (XO) to 30 mg apremilast tablets twice daily in the active treatment phase.

Number of subjects in period 2 ^[4]	Apremilast 20mg	Apremilast 30mg	Placebo/ 20mg Apremilast EE	Placebo / Apremilast 20 mg XO	Placebo / Apremilast 30 mg EE	Placebo / Apremilast 30 mg XO
Started	151	150	46	26	46	26
Completed	132	141	38	23	43	25
Not completed	19	9	8	3	3	1
Consent withdrawn by subject	11	2	-	-	1	1
Non-compliance with Study Drug	-	-	-	-	1	-
Adverse event, non-fatal	3	2	2	2	-	-
Unspecified	-	-	1	-	-	-
Lost to follow-up	-	-	2	-	-	-
Lack of efficacy	5	5	3	1	-	-
Protocol deviation	-	-	-	-	1	-

Notes
[4] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: For all the arms, the number of subjects starting the subsequent periods were less than or equal to the number completing the preceding period, this is because not all subjects who completed the preceding period would enter the subsequent period.

Period 3 title

Long-term Safety Phase (Year 2)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Not blinded

Are arms mutually exclusive

Yes

Apremilast 20mg

Arm description

Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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 30mg

Arm description

Participants initially randomized to receive 30 mg apremilast tablets twice daily in the 24-week placebo-controlled phase and continued to receive 30 mg apremilast tablets twice daily for up to 4.5 years 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

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

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

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

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

Number of subjects in period 3 ^[5]	Apremilast 20mg	Apremilast 30mg	Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]	Placebo/Apremilast 30 mg (Long-Term Safety Phase)
Started	122	134	57	67
Completed	99	109	48	60
Not completed	23	25	9	7
Noncompliance with Study Drug	-	1	-	-
Consent withdrawn by subject	13	12	3	2
Adverse event, non-fatal	2	7	1	1
Miscellaneous	1	-	1	1
Lack of efficacy	7	5	4	3

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 20mg

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 30mg

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

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

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

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

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

Number of subjects in period 4	Apremilast 20mg	Apremilast 30mg	Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]	Placebo/Apremilast 30 mg (Long-Term Safety Phase)
Started	99	109	48	60
Completed	90	91	40	49
Not completed	9	18	8	11
Noncompliance with Study Drug	1	1	-	-
Consent withdrawn by subject	2	8	2	4
Adverse event, non-fatal	1	2	3	4
Miscellaneous	1	-	1	-
Lost to follow-up	2	3	1	1
Lack of efficacy	2	4	1	2

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 20mg

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 30mg

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

Placebo/Apremilast 20 mg (LTSP)

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

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

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

Number of subjects in period 5 ^[6]	Apremilast 20mg	Apremilast 30mg	Placebo/Apremilast 20 mg (LTSP)	Placebo/Apremilast 30 mg (Long-Term Safety Phase)
Started	89	91	40	49
Completed	81	86	38	44
Not completed	8	5	2	5
Consent withdrawn by subject	5	4	1	4
Adverse event, non-fatal	2	-	-	-
Miscellaneous	-	-	1	-
Lost to follow-up	-	1	-	-
Lack of efficacy	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 20mg

Arm description

Participants initially randomized to receive 20 mg apremilast tablets twice daily in the 24-week placebo-controlled phase continued to receive 20 mg apremilast tablets twice daily for up to 4.5 years 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

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

Apremilast 30mg

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

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

Arm description

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

Arm type

Experimental

Investigational medicinal product name

CC-10004

Investigational medicinal product code

Other name

Otezla

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

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

Number of subjects in period 6	Apremilast 20mg	Apremilast 30mg	Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]	Placebo/Apremilast 30 mg (Long-Term Safety Phase)
Started	81	86	38	44
Completed	71	80	37	41
Not completed	10	6	1	3
Consent withdrawn by subject	6	2	-	1
Adverse event, non-fatal	1	1	-	1
Miscellaneous	-	2	1	1
Lost to follow-up	1	-	-	-
Lack of efficacy	2	1	-	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Apremilast 20mg

Reporting group description

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

Reporting group title

Apremilast 30mg

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 20mg	Apremilast 30mg	Total
Number of subjects	176	175	176	527
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)	160	159	161	480
From 65-84 years	16	16	15	47
85 years and over	0	0	0	0
Age Continuous
Units: years
arithmetic mean (standard deviation)	50.5 ± 11.58	49.2 ± 12.00	48.4 ± 12.52	-
Gender, Male/Female
Units: Subjects
Female	86	95	96	277
Male	90	80	80	250
Duration of Psoriatic Arthritis
Psoriatic arthritis (PsA) is a chronic and progressive inflammatory arthritis that, depending on the method of ascertainment, occurs in 6% to 39% of patients with psoriasis. Disease onset typically occurs between the ages of 30 and 55 years and affects both sexes equally. In the majority of patients, psoriasis precedes PsA by several years. The diagnosis of PsA is made on clinical grounds in patients with psoriasis having skin, scalp or nail changes.
Units: years
arithmetic mean (standard deviation)	3.42 ± 5.103	3.19 ± 4.706	3.62 ± 5.041	-

End points

Top of page

Reporting group title

Placebo

Reporting group description

Reporting group title

Apremilast 20mg

Reporting group description

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

Reporting group title

Apremilast 30mg

Reporting group description

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

Reporting group title

Apremilast 20mg

Reporting group description

Reporting group title

Apremilast 30mg

Reporting group description

Reporting group title

Placebo/ 20mg Apremilast EE

Reporting group description

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

Reporting group title

Placebo / Apremilast 20 mg XO

Reporting group description

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

Reporting group title

Placebo / Apremilast 30 mg EE

Reporting group description

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

Reporting group title

Placebo / Apremilast 30 mg XO

Reporting group description

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

Reporting group title

Apremilast 20mg

Reporting group description

Reporting group title

Apremilast 30mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

Reporting group description

Reporting group title

Apremilast 20mg

Reporting group description

Reporting group title

Apremilast 30mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

Reporting group description

Reporting group title

Apremilast 20mg

Reporting group description

Reporting group title

Apremilast 30mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg (LTSP)

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

Reporting group description

Reporting group title

Apremilast 20mg

Reporting group description

Reporting group title

Apremilast 30mg

Reporting group description

Reporting group title

Placebo/Apremilast 20 mg [Long-Term Safety Phase (LTSP)]

Reporting group description

Reporting group title

Placebo/Apremilast 30 mg (Long-Term Safety Phase)

Reporting group description

Subject analysis set title

Placebo / Apremilast 20 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants who received placebo twice daily up to Week 16 or Week 24 and were then re-randomized to receive 20 mg apremilast twice daily.

Subject analysis set title

Placebo / Apremilast 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants who received placebo twice daily up to Week 16 or Week 24 and were then re-randomized to receive 30 mg apremilast twice daily.

Subject analysis set title

Apremilast 20 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants initially randomized to receive apremilast 20 mg tablets twice daily.

Subject analysis set title

Apremilast 30 mg

Subject analysis set type

Full analysis

Subject analysis set description

Participants initially randomized to receive apremilast 30 mg tablets twice daily.

Subject analysis set title

Apremilast 20 mg (Pre-Switch)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who received 20 mg apremilast tablets twice daily, regardless of when the apremilast exposure started (at Week 0, 16 or 24). Only the TEAEs that occurred during apremilast 20 mg BID were counted.

Subject analysis set title

Apremilast 20/30 mg (Post-Switch)

Subject analysis set type

Safety analysis

Subject analysis set description

Participants who switched from apremilast 20 mg tablets twice daily to apremilast 30 mg twice daily. Only the TEAEs that occurred during the apremilast 30 mg 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 twice daily regardless of when the apremilast-exposure started (at Week 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

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 consisting of all subjects randomized as specified in the protocol; one participant randomized in error and did not receive any dose of investigational product (IP) was excluded. Participants who withdrew early or did not have sufficient data for a definitive 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	15.9	28.0	30.7

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 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[1]

P-value

= 0.0062

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

12.1

Confidence interval

level

95%

sides

2-sided

lower limit

3.5

upper limit

20.7

Notes
[1] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[2]

P-value

= 0.001

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

14.8

Confidence interval

level

95%

sides

2-sided

lower limit

6.1

upper limit

23.5

Notes
[2] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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 changes from baseline in the overall score indicate improvement in functional ability. Full analysis set; participants with a baseline value and at least 1 postbaseline 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 20mg	Apremilast 30mg
Number of subjects analysed	167	168	167
Units: units on a scale
least squares mean (standard error)	0.012 ± 0.0350	-0.156 ± 0.0349	-0.205 ± 0.0350

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 20mg

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[3]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.168

Confidence interval

level

95%

sides

2-sided

lower limit

-0.265

upper limit

-0.071

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

Statistical Analysis 2

Statistical analysis description

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[4]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.217

Confidence interval

level

95%

sides

2-sided

lower limit

-0.314

upper limit

-0.12

Notes
[4] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, and the baseline value as a covariate

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

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End point title

Percentage of Participants with an ACR 20 Response at Week 24

End point description

Percentage of participants with an American College of Rheumatology 20% (ACR20) response. A participant was a responder if the following 3 criteria for improvement from baseline were met: • ≥ 20% improvement in 78 tender joint count; • ≥ 20% improvement in 76 swollen joint count; and • ≥ 20% improvement in at least 3 of the 5 following parameters: Patient's assessment of pain (measured on a 100 mm visual analog scale [VAS]); Patient's global assessment of disease activity (measured on a 100 mm VAS); Physician's global assessment of disease activity (measured on a 100 mm VAS); Full analysis set; Participants who discontinued early, escaped 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	13.1	29.1	24.4

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[5]

P-value

= 0.0002 ^[6]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

16.1

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

24.4

Notes
[5] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
[6] - 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

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[7]

P-value

= 0.0063 ^[8]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

3.3

upper limit

19.4

Notes
[7] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
[8] - 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

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

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End point title

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

End point description

The 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 changes from Baseline in the overall score indicate improvement in functional ability. 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 20mg	Apremilast 30mg
Number of subjects analysed	167	169	167
Units: units on a scale
least squares mean (standard error)	0.012 ± 0.0370	-0.156 ± 0.0368	-0.207 ± 0.0369

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[9]

P-value

= 0.0014 ^[10]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.168

Confidence interval

level

95%

sides

2-sided

lower limit

-0.271

upper limit

-0.065

Notes
[9] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and baseline value as a covariate.
[10] - 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

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority ^[11]

P-value

< 0.0001 ^[12]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.219

Confidence interval

level

95%

sides

2-sided

lower limit

-0.322

upper limit

-0.117

Notes
[11] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and baseline value as a covariate.
[12] - 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

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). SF-36 domain scores were first calculated to range from 0 to100 and then transformed to norm-based scores (the norm-based scores in the US general population have an average of 50 and a standard deviation of 10). Norm-based scores were used in analyses, with higher scores indicating 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 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: units on a scale
least squares mean (standard error)	0.01 ± 0.588	2.39 ± 0.586	3.19 ± 0.590

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[13]

P-value

= 0.0043 ^[14]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

2.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.75

upper limit

4.01

Notes
[13] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and baseline value as a covariate
[14] - 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.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[15]

P-value

= 0.0002 ^[16]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

3.18

Confidence interval

level

95%

sides

2-sided

lower limit

1.55

upper limit

4.82

Notes
[15] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and baseline value as a covariate
[16] - 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

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=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	24.4	38.9	45.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[17]

P-value

= 0.0037 ^[18]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

14.4

Confidence interval

level

95%

sides

2-sided

lower limit

4.8

upper limit

Notes
[17] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
[18] - 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.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[19]

P-value

< 0.0001 ^[20]

Method

Chi-squared

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

11.3

upper limit

30.7

Notes
[19] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.
[20] - 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.

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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: mm
least squares mean (standard error)	-2.6 ± 1.81	-7.7 ± 1.79	-10.5 ± 1.80

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[21]

P-value

= 0.0485 ^[22]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-5

Confidence interval

level

95%

sides

2-sided

lower limit

-10

upper limit

Notes
[21] - Based on an analysis of covariance (ANCOVA) model with treatment group as a factor, and the baseline value as a covariate
[22] - 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

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[23]

P-value

= 0.0022 ^[24]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-7.8

Confidence interval

level

95%

sides

2-sided

lower limit

-12.8

upper limit

-2.8

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

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 Achilles 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 20mg	Apremilast 30mg
Number of subjects analysed	115	117	111
Units: units on a scale
least squares mean (standard error)	-0.5 ± 0.24	-0.5 ± 0.24	-1.5 ± 0.25

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority ^[25]

P-value

= 0.7696

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.8

upper limit

0.6

Notes
[25] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority ^[26]

P-value

= 0.0038 ^[27]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

-0.3

Notes
[26] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate
[27] - Secondary endpoints from the placebo-controlled period (Weeks 16 and 24) were analyzed in a hierarchical fashion to control the Type I error rate as described above

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 severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. Full analysis set. Participants with a baseline dactylitis severity score > 0 (i.e., pre-existing dactylitis) and at least 1 postbaseline value at or prior to Week 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline to Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	90	89	84
Units: units on a scale
least squares mean (standard error)	-1.0 ± 0.25	-1.9 ± 0.25	-1.7 ± 0.26

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[28]

Method

Parameter type

LS Mean Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

-0.2

Notes
[28] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[29]

Method

Parameter type

LS Mean Difference

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

Notes
[29] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor 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 20mg	Apremilast 30mg
Number of subjects analysed	163	166	164
Units: units on a scale
least squares mean (standard error)	-1.98 ± 0.770	-6.89 ± 0.763	-7.63 ± 0.768

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

329

Analysis specification

Pre-specified

Analysis type

superiority ^[30]

Method

Parameter type

LS Mean Difference

Point estimate

-4.91

Confidence interval

level

95%

sides

2-sided

lower limit

-7.04

upper limit

-2.78

Notes
[30] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

327

Analysis specification

Pre-specified

Analysis type

superiority ^[31]

Method

Parameter type

LS Mean Difference

Point estimate

-5.65

Confidence interval

level

95%

sides

2-sided

lower limit

-7.78

upper limit

-3.51

Notes
[31] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

Secondary: Change in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment

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End point title

Change in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment

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 16 are included. LOCF was used.

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	164	164	167
Units: units on a scale
least squares mean (standard error)	-0.15 ± 0.076	-0.61 ± 0.076	-0.68 ± 0.075

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

328

Analysis specification

Pre-specified

Analysis type

superiority ^[32]

Method

Parameter type

LS Mean Difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.67

upper limit

-0.25

Notes
[32] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

331

Analysis specification

Pre-specified

Analysis type

^[33]

Method

Parameter type

LS Mean Difference

Point estimate

-0.53

Confidence interval

level

95%

sides

2-sided

lower limit

-0.74

upper limit

-0.32

Notes
[33] - Based on analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor 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

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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 20mg	Apremilast 30mg
Number of subjects analysed	167	168	166
Units: units on a scale
least squares mean (standard error)	0.07 ± 0.631	1.19 ± 0.629	2.62 ± .0633

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

335

Analysis specification

Pre-specified

Analysis type

superiority ^[34]

Method

Parameter type

Difference in LS Means

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.63

upper limit

2.87

Notes
[34] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority ^[35]

Method

Parameter type

Difference in LS Means

Point estimate

2.55

Confidence interval

level

95%

sides

2-sided

lower limit

0.8

upper limit

4.31

Notes
[35] - Based on an analysis of covariance model for the change from baseline at Week 16, with treatment group as a factor 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

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End point title

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

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 QOL and consists of 36 questions in 8 domains (physical function, pain, general and mental health, vitality, social function, physical and emotional health). SF-36 domain scores were first calculated to range from 0 to100 and then transformed to norm-based scores (the norm-based scores in the US population have an average of 50 and a standard deviation of 10). Norm-based scores were used in analyses, with higher scores indicating 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. FAS; subjects 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 those who EE at Week 16.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: units on a scale
least squares mean (standard error)	0.16 ± 0.609	2.13 ± 0.605	3.88 ± 0.611

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[36]

Method

Parameter type

LS Means Difference

Point estimate

1.97

Confidence interval

level

95%

sides

2-sided

lower limit

0.28

upper limit

3.65

Notes
[36] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[37]

Method

Parameter type

LS Mean Difference

Point estimate

3.72

Confidence interval

level

95%

sides

2-sided

lower limit

2.02

upper limit

5.41

Notes
[37] - Based on an analysis of covariance model for the change from baseline at Week 24, with treatment group as a factor 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=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=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 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	17.0	36.6	35.2

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[38]

Method

Parameter type

Risk difference (RD)

Point estimate

19.5

Confidence interval

level

95%

sides

2-sided

lower limit

10.5

upper limit

28.6

Notes
[38] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[39]

Method

Parameter type

Risk difference (RD)

Point estimate

18.2

Confidence interval

level

95%

sides

2-sided

lower limit

9.2

upper limit

27.2

Notes
[39] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Secondary: Change from Baseline in Participants Assessment of Pain at Week 24

Top of page

End point title

Change from Baseline in Participants Assessment of Pain at Week 24

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	167	169	167
Units: mm
least squares mean (standard error)	-3.8 ± 1.83	-9.4 ± 1.82	-9.6 ± 1.83

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[40]

Method

Parameter type

LS Mean Difference

Point estimate

-5.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.6

upper limit

-0.5

Notes
[40] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority ^[41]

Method

Parameter type

LS Mean Difference

Point estimate

-5.7

Confidence interval

level

95%

sides

2-sided

lower limit

-10.8

upper limit

-0.7

Notes
[41] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor 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

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	111	113	106
Units: units on a scale
least squares mean (standard error)	-0.6 ± 0.25	-0.9 ± 0.25	-1.5 ± 0.26

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

224

Analysis specification

Pre-specified

Analysis type

superiority ^[42]

Method

Parameter type

LS Mean Difference

Point estimate

-0.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1

upper limit

0.4

Notes
[42] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

217

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.9

Confidence interval

level

95%

sides

2-sided

lower limit

-1.6

upper limit

-0.2

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 20mg	Apremilast 30mg
Number of subjects analysed	87	85	79
Units: units on a scale
least squares mean (standard error)	-1.0 ± 0.26	-2.0 ± 0.26	-1.7 ± 0.27

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

172

Analysis specification

Pre-specified

Analysis type

superiority ^[43]

Method

Parameter type

LS Mean Difference

Point estimate

-1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.7

upper limit

-0.3

Notes
[43] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

166

Analysis specification

Pre-specified

Analysis type

superiority ^[44]

Method

Parameter type

LS Mean Difference

Point estimate

-0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

0.1

Notes
[44] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: units on a scale
least squares mean (standard error)	-2.23 ± 0.807	-7.30 ± 0.803	-7.36 ± 0.810

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[45]

Method

Parameter type

LS Mean Difference

Point estimate

-5.07

Confidence interval

level

95%

sides

2-sided

lower limit

-7.31

upper limit

-2.84

Notes
[45] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[46]

Method

Parameter type

LS Mean Difference

Point estimate

-5.14

Confidence interval

level

95%

sides

2-sided

lower limit

-7.38

upper limit

-2.89

Notes
[46] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Secondary: Change in Disease Activity Score (DAS 28) at Week 24

Top of page

End point title

Change in Disease Activity Score (DAS 28) at Week 24

End point description

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	167	167	167
Units: units on a scale
least squares mean (standard error)	-0.22 ± 0.084	-0.69 ± 0.084	0.68 ± 0.084

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

LS Mean Difference

Point estimate

-0.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.7

upper limit

-0.23

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001 ^[47]

Method

ANCOVA

Parameter type

LS Mean Difference

Point estimate

-0.46

Confidence interval

level

95%

sides

2-sided

lower limit

-0.69

upper limit

-0.22

Notes
[47] - Based on an analysis of covariance (Ancova) model for the change from baseline at Week 24, with treatment group as a factor 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

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	167	169	166
Units: units on a scale
least squares mean (standard error)	0.25 ± 0.652	1.37 ± 0.648	2.58 ± 0.655

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

336

Analysis specification

Pre-specified

Analysis type

superiority ^[48]

Method

Parameter type

LS Mean Difference

Point estimate

1.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

2.93

Notes
[48] - Based on an analysis of covariance model (Ancova) for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

333

Analysis specification

Pre-specified

Analysis type

superiority ^[49]

Method

Parameter type

LS Mean difference

Point estimate

2.33

Confidence interval

level

95%

sides

2-sided

lower limit

0.52

upper limit

4.15

Notes
[49] - Based on an analysis of covariance model (Ancova) for the change from baseline at Week 24, with treatment group as a factor and the baseline value as a covariate.

Secondary: Percentage of Participants with ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score at Week 16

Top of page

End point title

Percentage of Participants with ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score 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 Achilles 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 20mg	Apremilast 30mg
Number of subjects analysed	115	117	111
Units: percentage of participants
number (not applicable)	46.1	48.7	63.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority ^[50]

Method

Parameter type

Risk difference (RD)

Point estimate

2.6

Confidence interval

level

95%

sides

2-sided

lower limit

-10.2

upper limit

15.5

Notes
[50] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority ^[51]

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

4.2

upper limit

29.8

Notes
[51] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Secondary: Percentage of Participants with Dactylitis Improvement ≥ 1 point at Week 16

Top of page

End point title

Percentage of Participants with Dactylitis Improvement ≥ 1 point at Week 16

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	90	89	84
Units: percentage of participants
number (not applicable)	60.0	66.3	61.9

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[52]

Method

Parameter type

Risk difference (RD)

Point estimate

6.3

Confidence interval

level

95%

sides

2-sided

lower limit

-7.8

upper limit

20.4

Notes
[52] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[53]

Method

Parameter type

Risk difference (RD)

Point estimate

1.9

Confidence interval

level

95%

sides

2-sided

lower limit

-12.6

upper limit

16.4

Notes
[53] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

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

The EULAR response criteria classify each subject as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject’s DAS28 as the measure of severity of disease. Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2. 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	25.0	41.1	44.3

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[54]

Method

Parameter type

Risk difference (RD)

Point estimate

16.1

Confidence interval

level

95%

sides

2-sided

lower limit

6.4

upper limit

25.8

Notes
[54] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[55]

Method

Parameter type

Risk difference (RD)

Point estimate

19.3

Confidence interval

level

95%

sides

2-sided

lower limit

9.6

upper limit

29.1

Notes
[55] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

Top of page

End point title

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

End point description

Percentage of participants with pre-existing enthesopathy whose MASES improved by ≥ 20% from Baseline after 24 weeks of treatment. The Maastricht Ankylosing Spondylitis Enthesitis Score quantitates inflammation of the entheses (enthesitis) by assessing pain at the following entheses (sites where tendons or ligaments insert into the bone): 1st costochondral joints left/right; 7th costochondral joints left/right; posterior superior iliac spine left/right; anterior superior iliac spine left/right; iliac crest left/right; 5th lumbar spinous process; and the proximal insertion of the Achilles tendon left/right. The MASES, ranging from 0 to 13, is the number of painful entheses out of 13 entheses.

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	115	117	111
Units: percentage of participants
number (not applicable)	48.7	54.7	66.7

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority ^[56]

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-6.8

upper limit

18.8

Notes
[56] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority ^[57]

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

5.3

upper limit

30.6

Notes
[57] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Secondary: Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 24

Top of page

End point title

Percentage of Participants with Dactylitis improvement ≥ 1 point at Week 24

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	90	89	84
Units: percentage of participants
number (not applicable)	57.8	69.7	63.1

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[58]

Method

Parameter type

Risk difference (RD)

Point estimate

11.9

Confidence interval

level

95%

sides

2-sided

lower limit

-2.1

upper limit

25.9

Notes
[58] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[59]

Method

Parameter type

Risk difference (RD)

Point estimate

5.3

Confidence interval

level

95%

sides

2-sided

lower limit

-9.2

upper limit

19.8

Notes
[59] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

The EULAR response reflects an improvement in disease activity and an attainment of a lower degree of disease activity based on th DAS-28. Good or moderate response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 Moderate response: DAS28 at the time point > 3.2 and improvement from baseline > 1.2, or DAS28 at the time point ≤ 5.1 and improvement from baseline > 0.6 and ≤ 1.2 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	17.0	34.9	28.4

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[60]

Method

Parameter type

Risk difference (RD)

Point estimate

17.8

Confidence interval

level

95%

sides

2-sided

lower limit

8.8

upper limit

26.8

Notes
[60] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[61]

Method

Parameter type

Risk difference (RD)

Point estimate

11.4

Confidence interval

level

95%

sides

2-sided

lower limit

2.7

upper limit

Notes
[61] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

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End point title

Percentage of Participants with a ACR 50 Response at Week 16

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: Percentage of participants
number (not applicable)	4.5	11.4	11.4

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[62]

Method

Parameter type

Risk difference (RD)

Point estimate

6.9

Confidence interval

level

95%

sides

2-sided

lower limit

1.3

upper limit

12.5

Notes
[62] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[63]

Method

Parameter type

Risk difference (RD)

Point estimate

6.8

Confidence interval

level

95%

sides

2-sided

lower limit

1.2

upper limit

12.4

Notes
[63] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Secondary: Percentage of Participants with a ACR 70 response at Week 16

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End point title

Percentage of Participants with a ACR 70 response at Week 16

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	1.1	4.0	4.0

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[64]

Method

Parameter type

Risk difference (RD)

Point estimate

2.9

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

6.2

Notes
[64] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[65]

Method

Parameter type

Risk difference (RD)

Point estimate

2.8

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

6.1

Notes
[65] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Secondary: Percentage of Participants with a ACR 50 response at Week 24

Top of page

End point title

Percentage of Participants with a ACR 50 response at Week 24

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 24

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	6.3	16.0	12.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[66]

Method

Parameter type

Risk difference (RD)

Point estimate

9.8

Confidence interval

level

95%

sides

2-sided

lower limit

3.2

upper limit

16.3

Notes
[66] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[67]

Method

Parameter type

Risk difference (RD)

Point estimate

6.3

Confidence interval

level

95%

sides

2-sided

lower limit

0.2

upper limit

12.3

Notes
[67] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	176
Units: percentage of participants
number (not applicable)	4.0	4.0	4.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

351

Analysis specification

Pre-specified

Analysis type

superiority ^[68]

Method

Parameter type

Risk difference (RD)

Point estimate

Confidence interval

level

95%

sides

2-sided

lower limit

-4.1

upper limit

4.1

Notes
[68] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

352

Analysis specification

Pre-specified

Analysis type

superiority ^[69]

Method

Parameter type

Risk difference (RD)

Point estimate

0.6

Confidence interval

level

95%

sides

2-sided

lower limit

-3.7

upper limit

4.8

Notes
[69] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Secondary: Percentage of Participants with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 at Week 16

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End point title

Percentage of Participants with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 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 Achilles 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 20mg	Apremilast 30mg
Number of subjects analysed	115	117	111
Units: percentage of participants
number (not applicable)	19.1	21.4	36.9

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority ^[70]

Method

Parameter type

Risk difference (RD)

Point estimate

2.2

Confidence interval

level

95%

sides

2-sided

lower limit

-8.1

upper limit

12.6

Notes
[70] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority ^[71]

Method

Parameter type

Risk difference (RD)

Point estimate

17.8

Confidence interval

level

95%

sides

2-sided

lower limit

6.3

upper limit

29.3

Notes
[71] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 at Week 16

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End point title

Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 at Week 16

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 16

End point values	Placebo	Apremilast 20mg	Apremilast 30mg
Number of subjects analysed	90	89	84
Units: percentage of participants
number (not applicable)	33.3	42.7	40.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[72]

Method

Parameter type

Risk difference (RD)

Point estimate

9.4

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

23.5

Notes
[72] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[73]

Method

Parameter type

Risk difference (RD)

Point estimate

7.1

Confidence interval

level

95%

sides

2-sided

lower limit

-7.2

upper limit

21.5

Notes
[73] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution

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

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 Achilles 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 (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 20mg	Apremilast 30mg
Number of subjects analysed	115	117	111
Units: percentage of participants
number (not applicable)	22.6	29.1	37.8

Statistical Analysis 1

Statistical analysis description

Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

232

Analysis specification

Pre-specified

Analysis type

superiority

Method

Parameter type

Risk difference (RD)

Point estimate

6.5

Confidence interval

level

95%

sides

2-sided

lower limit

-4.8

upper limit

17.7

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

226

Analysis specification

Pre-specified

Analysis type

superiority ^[74]

Method

Parameter type

Risk difference (RD)

Point estimate

15.2

Confidence interval

level

95%

sides

2-sided

lower limit

3.4

upper limit

27.1

Notes
[74] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

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End point title

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

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 24 weeks of treatment. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. 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 20mg	Apremilast 30mg
Number of subjects analysed	90	89	84
Units: percentage of participants
number (not applicable)	35.6	46.1	40.5

Statistical Analysis 1

Comparison groups

Placebo v Apremilast 20mg

Number of subjects included in analysis

179

Analysis specification

Pre-specified

Analysis type

superiority ^[75]

Method

Parameter type

Risk difference (RD)

Point estimate

10.5

Confidence interval

level

95%

sides

2-sided

lower limit

-3.8

upper limit

24.8

Notes
[75] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

Statistical Analysis 2

Comparison groups

Placebo v Apremilast 30mg

Number of subjects included in analysis

174

Analysis specification

Pre-specified

Analysis type

superiority ^[76]

Method

Parameter type

Risk difference (RD)

Point estimate

4.9

Confidence interval

level

95%

sides

2-sided

lower limit

-9.5

upper limit

19.3

Notes
[76] - Two-sided 95% CI of the proportion difference is based on the normal approximation to the binomial distribution.

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

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. 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. 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	62	67	131	138
Units: Percentage of Participants
number (confidence interval 95%)	59.7 (46.4 to 71.9)	56.7 (44.0 to 68.8)	53.4 (44.5 to 62.2)	58.7 (50.0 to 67.0)

No statistical analyses for this end point

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

Top of page

End point title

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

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 changes from Baseline in the overall score indicate improvement in functional ability. 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	62	68	132	139
Units: units on a scale
arithmetic mean (standard deviation)	-0.21 ± 0.450	-0.25 ± 0.533	-0.32 ± 0.559	-0.39 ± 0.567

No statistical analyses for this end point

Secondary: Change From Baseline in the SF-36v2 Physical Functioning Scale Score at Week 52

Top of page

End point title

Change From Baseline in the SF-36v2 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	62	68	132	139
Units: units on a scale
arithmetic mean (standard deviation)	7.76 ± 8.236	6.87 ± 7.241	5.68 ± 8.467	5.87 ± 8.008

No statistical analyses for this end point

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

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End point title

Percentage of Participants with a Modified PsARC Response at Week 52

End point description

Measure 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=lowest disease activity and 100=highest; • Physician global assessment of disease activity, measured on a 100 mm VAS, where 0=lowest disease activity and 100=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. 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	61	67	131	137
Units: Percentage of Participants
number (confidence interval 95%)	73.8 (60.9 to 84.2)	79.1 (67.4 to 88.1)	75.6 (67.3 to 82.7)	75.9 (67.9 to 82.8)

No statistical analyses for this end point

Secondary: Change from Baseline in the Participants Assessment of Pain using the Visual Analog Scale at Week 52

Top of page

End point title

Change from Baseline in the Participants Assessment of Pain using the Visual Analog Scale 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	62	68	132	139
Units: mm
arithmetic mean (standard deviation)	-13.1 ± 25.57	-18.9 ± 24.28	-15.6 ± 27.29	-14.2 ± 28.14

No statistical analyses for this end point

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

Top of page

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 Achilles 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	41	42	91	85
Units: units on a scale
arithmetic mean (standard deviation)	-1.7 ± 2.38	-1.8 ± 2.34	-1.5 ± 2.62	-1.8 ± 3.03

No statistical analyses for this end point

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

Top of page

End point title

Change From Baseline in the Dactylitis Severity Score at Week 52

End point description

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

End point type

Secondary

End point timeframe

Baseline and Week 52

End point values	Placebo / Apremilast 20 mg	Placebo / Apremilast 30 mg	Apremilast 20 mg	Apremilast 30 mg
Number of subjects analysed	32	38	70	64
Units: units on a scale
arithmetic mean (standard deviation)	-2.2 ± 1.89	2.9 ± 2.47	-2.2 ± 4.09	-2.9 ± 3.55

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	61	67	131	137
Units: units on a scale
arithmetic mean (standard deviation)	-11.0 ± 10.288	-14.67 ± 11.943	-14.32 ± 11.128	-13.98 ± 10.541

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	62	68	130	138
Units: units on a scale
arithmetic mean (standard deviation)	-1.08 ± 1.113	-1.28 ± 1.044	-1.37 ± 1.128	-1.39 ± 0.970

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	62	67	131	139
Units: units on a scale
arithmetic mean (standard deviation)	6.03 ± 8.787	4.27 ± 9.461	2.39 ± 10.197	5.89 ± 10.471

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 Achilles 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 MASES > 0 (i.e., pre-existing enthesopathy) 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	41	42	91	85
Units: Percentage of Participants
number (confidence interval 95%)	70.0 (54.5 to 83.9)	81.0 (65.9 to 91.4)	65.9 (55.3 to 75.5)	69.4 (58.5 to 79.0)

No statistical analyses for this end point

Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline by ≥ 1 at Week 52

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End point title

Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline by ≥ 1 at Week 52

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improved by ≥ 1 after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. 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	32	38	70	64
Units: Percentage of Participants
number (confidence interval 95%)	93.8 (79.2 to 99.2)	94.7 (82.3 to 99.4)	87.1 (77.0 to 93.9)	85.9 (75.0 to 93.4)

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

The EULAR response criteria classify each subject as a good, moderate or non-responder to treatment based on the degree of improvement from baseline and the level of disease activity at the endpoint. EULAR response is derived using the individual subject’s DAS28 as the measure of severity of disease. A Good response is defined as follows: Good response: DAS28 at the time point ≤ 3.2 and improvement from baseline > 1.2 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	62	68	130	138
Units: Percentage of Participants
number (not applicable)	64.5	73.5	75.4	79.0

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

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]); 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. 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 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	62	67	129	138
Units: Percentage of Participants
number (confidence interval 95%)	30.6 (19.6 to 43.7)	25.4 (15.5 to 37.5)	27.1 (19.7 to 35.7)	31.9 (24.2 to 40.4)

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

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. 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	61	68	131	138
Units: Percentage of Participants
number (confidence interval 95%)	8.2 (2.7 to 18.1)	10.3 (4.2 to 20.1)	13.7 (8.4 to 20.8)	18.1 (12.1 to 25.6)

No statistical analyses for this end point

Secondary: Percentage of Participants with Pre-existing Enthesopathy whose MASES Improves from Baseline to 0 at Week 52

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End point title

Percentage of Participants with Pre-existing Enthesopathy whose MASES Improves from Baseline to 0 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 Achilles 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; only those participants with a baseline value > 0 (i.e., pre-existing enthesopathy) 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	41	42	91	85
Units: percentage of participants
number (confidence interval 95%)	39.0 (24.2 to 55.5)	61.9 (45.6 to 76.4)	39.6 (29.5 to 50.4)	45.9 (35.0 to 57.0)

No statistical analyses for this end point

Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline to 0 at Week 52

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End point title

Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves from Baseline to 0 at Week 52

End point description

Percentage of participants with pre-existing dactylitis whose dactylitis severity score improves to zero after 52 weeks. Dactylitis is characterized by swelling of the entire finger or toe. Each digit on the hands and feet was rated as zero for no dactylitis or 1 for dactylitis present. The dactylitis severity score is the sum of the individual scores for each digit. The dactylitis severity score, ranging from 0 to 20, is the number of digits on the hands and feet with dactylitis present. 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	32	38	70	64
Units: Percentage of Participants
number (confidence interval 95%)	75.0 (56.6 to 88.5)	78.9 (62.7 to 90.4)	68.6 (56.4 to 79.1)	68.8 (55.9 to 79.8)

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 TEAE is an adverse event (AE) with a start date on or after the date of the first dose of investigational product (IP) and no later than 28 days after the last dose of IP. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. A serious AE is any AE that results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. For both AEs and SAEs the investigator assessed the severity of the event according to the grading scale: Mild: asymptomatic or with mild symptoms, Moderate: symptoms causing moderate discomfort or Severe: symptoms causing severe discomfort or pain. Safety population included 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 20mg	Apremilast 30mg
Number of subjects analysed	176	175	175
Units: Participants
Any TEAE	73	87	99
Any Drug-Related TEAE	25	40	58
Any Severe TEAE	6	4	2
Any Serious TEAE (SAE)	5	3	1
Drug-Related (SAE)	0	0	1
Any TEAE Leading to Drug Interruption	8	11	0
Any TEAE Leading to Drug Wirhdrawal	4	4	6
Any TEAE Leading to Death	0	0	0

No statistical analyses for this end point

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

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End point title

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

End point description

A TEAE is an AE with a start date on or after the date of the first dose of IP and no later than 28 days after the last dose. An AE is any noxious, unintended, or untoward medical occurrence that may appear or worsen in a subject during the course of a study. A SAE = AE that results in death; is life-threatening; requires inpatient hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; or constitutes an important medical event. For both AEs and SAEs the severity of the event was applied to the grading scale: Mild: asymptomatic or with mild symptoms, Moderate: symptoms causing moderate discomfort or Severe: symptoms causing severe discomfort. Apremilast Subjects as Treated (AAT) received at least 1 dose of APR at any time during the study. Subjects were included in the treatment group corresponding to the APR dosing regimen they received, irrespective of the treatment group to which they were randomized or re-randomized.

End point type

Secondary

End point timeframe

Week 0 to Week 260; median duration of exposure to apremilast 20 mg BID was 168.93 weeks and 229.36 weeks for apremilast 30 mg BID

End point values	Apremilast 20 mg (Pre-Switch)	Apremilast 20/30 mg (Post-Switch)	Apremilast 30 mg
Number of subjects analysed	252	122	252
Units: Participants
Any TEAE	188	60	204
Any Drug-Related TEAE	89	16	113
Any Severe TEAE	24	3	23
Any Serious TEAE (SAE)	35	5	36
Drug-Related (SAE)	6	1	6
Any TEAE Leading to Drug Interruption	41	5	36
Any TEAE Leading to Drug Wirhdrawal	22	2	26
Any TEAE Leading to Death	0	0	0

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 to Week 16 for placebo subjects who entered EE at Week 16 and up to Week 24 for all others and reported for the Apremilast Exposure Period from Week 0 to Week 260

Adverse event reporting additional description

Median duration of APR 20 mg BID was 168.93 weeks and 229.36 weeks for apremilast 30 mg twice daily

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 twice daily during the 24-week placebo-controlled phase.

Reporting group title

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

Reporting group description

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

Reporting group title

APR Exposure Period Up to 5 Years: Apremilast 20 mg

Reporting group description

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

Reporting group title

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

Reporting group description

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

Reporting group title

APR Exposure Period Up to 5 Years: Apremilast 30 mg

Reporting group description

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

Serious adverse events	Weeks 0-24: Placebo (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 20 mg (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 30 mg (Placebo-Controlled Phase)	APR Exposure Period Up to 5 Years: Apremilast 20 mg	APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg	APR Exposure Period Up to 5 Years: Apremilast 30 mg
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 176 (2.84%)	3 / 175 (1.71%)	1 / 175 (0.57%)	35 / 252 (13.89%)	5 / 122 (4.10%)	36 / 252 (14.29%)
number of deaths (all causes)	0	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervix carcinoma stage 0
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Lung squamous cell carcinoma stage unspecified
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Papilloma
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Prostate cancer
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Femoral artery occlusion
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Varicose vein
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Non-cardiac chest pain
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Reproductive system and breast disorders
Cystocele
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Endometrial atrophy
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Endometrial hyperplasia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	0 / 252 (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
Metrorrhagia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Postmenopausal haemorrhage
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Rectocele
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Asthma
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Haemoptysis
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	0 / 252 (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
Nasal polyps
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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 embolism
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Confusional state
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Investigations
Alanine aminotransferase increased
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Aspartate aminotransferase increased
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Injury, poisoning and procedural complications
Contusion
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Incisional hernia
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	1 / 122 (0.82%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 3	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Multiple fractures
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Multiple injuries
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Post procedural fistula
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Radius fracture
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Road traffic accident
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Tibia fracture
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute myocardial infarction
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Angina pectoris
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Atrial fibrillation
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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 flutter
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	2 / 252 (0.79%)
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
Atrioventricular block
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Atrioventricular block second degree
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Coronary artery disease
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Palpitations
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Pericarditis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Stress cardiomyopathy
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Nervous system disorders
Carpal tunnel syndrome
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Epilepsy
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Sciatica
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Spinal cord compression
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Transient ischaemic attack
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	2 / 252 (0.79%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo CNS origin
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Lymphadenopathy mediastinal
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
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 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Retinal vein thrombosis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Gastrointestinal disorders
Abdominal pain lower
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Anal fissure
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Diarrhoea
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Enterocele
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	1 / 122 (0.82%)	3 / 252 (1.19%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Rectal haemorrhage
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Umbilical hernia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	2 / 252 (0.79%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	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
Psoriasis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	2 / 252 (0.79%)
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
Renal and urinary disorders
Calculus ureteric
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Hydronephrosis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Nephrolithiasis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyuria
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Arthralgia
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Back pain
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	2 / 252 (0.79%)	0 / 122 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc disorder
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Musculoskeletal pain
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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 stiffness
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Psoriatic arthropathy
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	2 / 252 (0.79%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Infections and infestations
Chronic sinusitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic tonsillitis
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Clostridium difficile colitis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	1 / 122 (0.82%)	0 / 252 (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
Diabetic gangrene
subjects affected / exposed	1 / 176 (0.57%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	0 / 252 (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
Gallbladder empyema
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Lower respiratory tract infection
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Meningitis bacterial
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	1 / 122 (0.82%)	0 / 252 (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
Pelvic abscess
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Pneumococcal bacteraemia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	1 / 122 (0.82%)	0 / 252 (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
Pneumonia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	1 / 122 (0.82%)	0 / 252 (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
Pyelonephritis
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pyelonephritis acute
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	1 / 175 (0.57%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Urinary tract infection bacterial
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
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
Metabolism and nutrition disorders
Hypocalcaemia
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	1 / 252 (0.40%)	0 / 122 (0.00%)	0 / 252 (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
Obesity
subjects affected / exposed	0 / 176 (0.00%)	0 / 175 (0.00%)	0 / 175 (0.00%)	0 / 252 (0.00%)	0 / 122 (0.00%)	1 / 252 (0.40%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Weeks 0-24: Placebo (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 20 mg (Placebo-Controlled Phase)	Weeks 0-24: Apremilast 30 mg (Placebo-Controlled Phase)	APR Exposure Period Up to 5 Years: Apremilast 20 mg	APR Exposure Period Up to 5 Years: Apremilast 20mg/30 mg	APR Exposure Period Up to 5 Years: Apremilast 30 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	30 / 176 (17.05%)	51 / 175 (29.14%)	65 / 175 (37.14%)	121 / 252 (48.02%)	24 / 122 (19.67%)	141 / 252 (55.95%)
Vascular disorders
Hypertension
subjects affected / exposed	1 / 176 (0.57%)	4 / 175 (2.29%)	4 / 175 (2.29%)	15 / 252 (5.95%)	0 / 122 (0.00%)	16 / 252 (6.35%)
occurrences all number	1	4	4	15	0	19
Nervous system disorders
Headache
subjects affected / exposed	4 / 176 (2.27%)	6 / 175 (3.43%)	15 / 175 (8.57%)	15 / 252 (5.95%)	0 / 122 (0.00%)	26 / 252 (10.32%)
occurrences all number	4	6	16	15	0	32
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	3 / 176 (1.70%)	12 / 175 (6.86%)	21 / 175 (12.00%)	30 / 252 (11.90%)	2 / 122 (1.64%)	31 / 252 (12.30%)
occurrences all number	3	13	24	34	4	48
Dyspepsia
subjects affected / exposed	2 / 176 (1.14%)	8 / 175 (4.57%)	0 / 175 (0.00%)	14 / 252 (5.56%)	0 / 122 (0.00%)	4 / 252 (1.59%)
occurrences all number	2	11	0	19	0	4
Nausea
subjects affected / exposed	5 / 176 (2.84%)	16 / 175 (9.14%)	28 / 175 (16.00%)	24 / 252 (9.52%)	2 / 122 (1.64%)	39 / 252 (15.48%)
occurrences all number	5	17	30	27	2	51
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 176 (1.14%)	6 / 175 (3.43%)	4 / 175 (2.29%)	11 / 252 (4.37%)	1 / 122 (0.82%)	13 / 252 (5.16%)
occurrences all number	2	6	4	13	1	14
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	6 / 176 (3.41%)	1 / 175 (0.57%)	2 / 175 (1.14%)	6 / 252 (2.38%)	1 / 122 (0.82%)	13 / 252 (5.16%)
occurrences all number	6	1	2	8	1	16
Psychiatric disorders
Depression
subjects affected / exposed	1 / 176 (0.57%)	1 / 175 (0.57%)	2 / 175 (1.14%)	5 / 252 (1.98%)	2 / 122 (1.64%)	13 / 252 (5.16%)
occurrences all number	1	1	2	5	2	14
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	0 / 176 (0.00%)	1 / 175 (0.57%)	3 / 175 (1.71%)	14 / 252 (5.56%)	0 / 122 (0.00%)	10 / 252 (3.97%)
occurrences all number	0	1	3	15	0	11
Infections and infestations
Nasopharyngitis
subjects affected / exposed	3 / 176 (1.70%)	3 / 175 (1.71%)	3 / 175 (1.71%)	20 / 252 (7.94%)	5 / 122 (4.10%)	23 / 252 (9.13%)
occurrences all number	3	3	3	26	6	50
Sinusitis
subjects affected / exposed	1 / 176 (0.57%)	6 / 175 (3.43%)	4 / 175 (2.29%)	16 / 252 (6.35%)	6 / 122 (4.92%)	12 / 252 (4.76%)
occurrences all number	1	6	4	18	7	15
Upper respiratory tract infection
subjects affected / exposed	4 / 176 (2.27%)	6 / 175 (3.43%)	7 / 175 (4.00%)	26 / 252 (10.32%)	5 / 122 (4.10%)	31 / 252 (12.30%)
occurrences all number	4	6	8	31	5	41
Urinary tract infection
subjects affected / exposed	1 / 176 (0.57%)	2 / 175 (1.14%)	2 / 175 (1.14%)	10 / 252 (3.97%)	3 / 122 (2.46%)	18 / 252 (7.14%)
occurrences all number	1	2	2	15	3	27

More information

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Were there any global substantial amendments to the protocol? Yes

24 Jan 2011

1. Clarified that the modified ACR 20 (primary endpoint) is one of the tools that is listed as acceptable by the European Medicines Agency Guideline on Clinical Investigation of Medicinal Products Indicated for the Treatment of Psoriatic Arthritis. 2. Added BSA involved by psoriasis as a study assessment. 3. Clarified the language related to contraception methods in several protocol sections to ensure that the acceptable methods of contraception were precisely described and added a statement to ensure that the investigator provided appropriate education regarding acceptable contraceptive methods to the subjects. 4. Deleted the requirement for annual chest radiographs to allow local treatment guidelines to dictate when chest radiographs would be performed. 5. Modified the reasons for discontinuation of the IP (apremilast or placebo) or from the study to include “noncompliance with study drug” and “study terminated by sponsor” for alignment with the reasons that were actually displayed in the InForm database. 6. Clarified that informed consent must be obtained from the study subject or from a legal representative before any study-related procedures were performed. 7. Clarified the exclusion criteria related to psoriasis (Exclusion Criterion 16) and added fibromyalgia as an exclusion criterion (to Exclusion Criterion 18). 8. Modified the exclusion criterion related to prior malignancy. 9. Provided further clarification of prohibited concomitant medications

10 Jun 2011

1. Added a serum pregnancy test for FCBP at baseline. 2. Clarified that microscopic evaluation must be performed on all urine specimens. 3. Clarified the inclusion criteria (Inclusion Criterion 14) to indicate that the chosen form of birth contraception must be fully effective by the time the FCBP receive the first dose of IP at randomization. 4. Clarified the inclusion criterion (Inclusion Criterion 13) to indicate that male subjects must use a “male” latex or nonlatex (not made of natural membrane) condom. 5. Added “at randomization” to the text of exclusion criterion. 6. Deleted text related to the manner in which the onset and end dates of SAEs were to be recorded on the SAE Report Form (no longer applicable). 7. Corrected the name of the Celgene Therapeutic Area Head. 8. Corrected the timing of Visit 6 from Week 32 to Week 28 in the Table of Events.

20 Apr 2012

1. Modified the treatment and administration schedule to state that the site personnel and subjects would remain blinded to the treatment assignments until all of the subjects had completed the 52-week double-blind phase of the study. 2. Replaced the SRP with an independent external DMC. 3. Revised the protocol to permit subjects who experienced worsening of skin psoriasis to receive topical therapy or phototherapy after completion of the 52-week double blind study period. 4. Added an assessment of vasculitis and a psychiatric evaluation as part of the AE assessments and provided guidance related to the medical management of these conditions to the investigators. 5. Added radiographic evaluations of symptomatic joints, as medically indicated, during the long-term extension phase of the study. 6. Revised inclusion criteria 13 and 14 and the section on contraception education to reflect the change in the protocol requirements for contraception. 7. Provided information on the manner in which apremilast would be supplied during the open-label extension phase of the study (ie, after Week 52). 8. Specified that the AE tables would only summarize TEAEs. 9. Changed “CRF” to “eCRF” to reflect that the study data were to be captured on electronic CRFs. 10. Incorporated several administrative changes to the Table of Events to reflect changes that were made in other sections of the protocol. 11. Updated the name and contact information of the PPD Medical Monitor.

03 Jul 2012

1. Changed the assessment of the primary endpoint (modified ACR 20) from Week 24 to Week 16. 2. Elevated assessments of enthesitis and dactylitis (in subjects who presented with these manifestations of PsA at baseline) from exploratory endpoints to secondary endpoints. 3. Added an assessment of the secondary endpoints at Week 16 (in addition to Weeks 24 and 52). 4. Changed the order of secondary endpoints at Weeks 16, 24, and 52 to coincide with the planned sequence of statistical testing. 5. Added the modified PsARC response and EULAR response as secondary endpoints. 6. Added the ACR-N as an exploratory endpoint. 7. Added an assessment of the health-related quality of life endpoints at Week 16 (in addition to Weeks 24 and 52). 8. Modified the permitted concomitant medications to allow use of systemic corticosteroids and DMARDs for the treatment of worsening arthritic symptoms of PsA after the Week 52 visit. 9. Revised the statistical approaches for the secondary endpoints and for the subgroup analyses.

20 Dec 2012

1. Extended the maximum duration of treatment from 2 years to 5 years to allow evaluation of the efficacy, safety, and tolerability of apremilast for up to 5 years in subjects with active PsA. 2. Changed the last visit from Visit 13 to Visit 25 as a result of the study extension. 3. Added references for the modified PsARC and EULAR response (added as secondary efficacy outcome measures). An administrative letter (dated 22 Feb 2012) was issued to correct the timing of the PASI in the Table of Events (removed from Visit 7).

Were there any global interruptions to the trial? No

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

None reported

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Clinical trials

Clinical Trial Results: A 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 Who Have Not Been Previously Treated with Disease-modifying Antirheumatic Drugs

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 in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment

Secondary: Change in Baseline in the Disease Activity Score (DAS28) after 16 Weeks of Treatment

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 Participants Assessment of Pain at Week 24

Secondary: Change from Baseline in Participants 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 in Disease Activity Score (DAS 28) at Week 24

Secondary: Change in Disease Activity Score (DAS 28) 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 ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score at Week 16

Secondary: Percentage of Participants with ≥ 20% Improvement in Maastricht Ankylosing Spondylitis Entheses Score 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 a ACR 70 response at Week 16

Secondary: Percentage of Participants with a ACR 70 response at Week 16

Secondary: Percentage of Participants with a ACR 50 response at Week 24

Secondary: Percentage of Participants with a 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 with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 at Week 16

Secondary: Percentage of Participants with Pre-existing Enthesopathy whose Maastricht Ankylosing Spondylitis Entheses Score Improves to 0 at Week 16

Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 at Week 16

Secondary: Percentage of Participants with Pre-existing Dactylitis whose Dactylitis Severity Score Improves to 0 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 Who Have Not Been Previously Treated with Disease-modifying Antirheumatic Drugs