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Clinical Trial Results:
A Phase III randomized, double-blind, placebo-controlled multicenter study of subcutaneous secukinumab in prefilled syringes to demonstrate the efficacy at 24 weeks and to assess the long term efficacy, safety and tolerability up to 5 years in patients with Active Psoriatic Arthritis

Summary
EudraCT number	2012-004439-22
Trial protocol	GB BE CZ DE PL
Global end of trial date	09 Jan 2019

Results information
Results version number	v1(current)
This version publication date	01 Jan 2020
First version publication date	01 Jan 2020
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

CAIN457F2312

ISRCTN number

US NCT number

NCT01752634

WHO universal trial number (UTN)

Sponsor organisation name

Novartis Pharma AG

Sponsor organisation address

CH-4002, Basel, Switzerland,

Public contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.com

Scientific contact

Clinical Disclosure Office, Novartis Pharma AG, 41 613241111, Novartis.email@novartis.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

09 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

09 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to demonstrate that the efficacy of secukinumab 75 mg or 150 mg or 300 mg at Week 24 is superior to placebo in patients with active psoriatic arthritis (PsA) based on the proportion of patients achieving an American College of Rheumatology 20 (ACR20) response.

Protection of trial subjects

The study was in compliance with the ethical principles derived from the Declaration of Helsinki and the International Conference on Harmonization (ICH) Good Clinical Practice (GCP) guidelines. All the local regulatory requirements pertinent to safety of trial subjects were also followed during the conduct of the trial.

Background therapy

Evidence for comparator

Actual start date of recruitment

14 Apr 2013

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 39

Country: Number of subjects enrolled

Belgium: 7

Country: Number of subjects enrolled

Canada: 26

Country: Number of subjects enrolled

Czech Republic: 43

Country: Number of subjects enrolled

Germany: 23

Country: Number of subjects enrolled

United Kingdom: 44

Country: Number of subjects enrolled

Poland: 40

Country: Number of subjects enrolled

Russian Federation: 65

Country: Number of subjects enrolled

Thailand: 5

Country: Number of subjects enrolled

United States: 105

Worldwide total number of subjects

397

EEA total number of subjects

157

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)

364

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

The study population was comprised of subjects who had passed screening assessments, complied with eligibility criteria and had provided written consent.

Screening details

At baseline, all eligible subjects were randomized via Interactive Response Technology (IRT) to one of the 4 treatment arms. At Week 16, Subjects on Placebo were rerandomized to receive secukinumab 150 mg s.c. or 300 mg s.c. from Week 16 (non-responder) or Week 24 (responder).

Period 1 title

Up to Week 24 (Primary Analysis)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Are arms mutually exclusive

Yes

Secukinumab (AIN457) 75 mg s.c.

Arm description

Group 1- Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 75 mg s.c.

Secukinumab (AIN457) 150 mg s.c.

Arm description

Group 2 - Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 150 mg s.c.

Secukinumab (AIN457) 300 mg s.c.

Arm description

Group 3 - Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 300 mg s.c.

Placebo

Arm description

Placebo - rerandomized at Week 16 to receive secukinumab 150 mg s.c. or 300 mg s.c. from Week 16 (nonresponder) or Week 24 (responder).

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 0 mg s.c.

Number of subjects in period 1	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Started	99	100	100	98
Completed	93	95	97	88
Not completed	6	5	3	10
Physician decision	-	1	-	-
Adverse event, non-fatal	3	-	2	4
Subject/guardian decision	1	1	1	3
Lack of efficacy	2	3	-	3

Period 2 title

Week 24 to Week 260

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Data analyst

Blinding implementation details

The study was open label label after Week 52 analysis was completed.

Are arms mutually exclusive

Yes

Secukinumab (AIN457) 75 mg s.c.

Arm description

Group 1- Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled pen, Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 75 mg s.c.

Secukinumab (AIN457) 150 mg s.c.

Arm description

Group 2 - Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 150 mg s.c.

Secukinumab (AIN457) 300 mg s.c.

Arm description

Group 3 - Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 300 mg s.c.

Placebo - AIN457 150 mg

Arm description

Placebo - rerandomized to AIN457 150 mg

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 150 mg s.c.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 0 mg s.c.

Placebo - AIN457 300 mg

Arm description

Placebo - rerandomized to AIN457 300 mg

Arm type

Experimental

Investigational medicinal product name

Secukinumab

Investigational medicinal product code

AIN457

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 300 mg s.c.

Investigational medicinal product name

Placebo

Investigational medicinal product code

Placebo

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Secukinumab 0 mg s.c.

Number of subjects in period 2	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo - AIN457 150 mg	Placebo - AIN457 300 mg
Started	93	95	97	43	45
Completed	59	65	64	29	31
Not completed	34	30	33	14	14
Adverse event, serious fatal	-	1	-	-	-
Physician decision	1	2	4	2	1
Noncompliance with study treatment	-	-	1	-	-
Adverse event, non-fatal	4	8	8	4	2
Pregnancy	-	-	1	-	-
Lost to follow-up	2	2	3	-	2
Subject/guardian decision	12	10	9	5	5
Lack of efficacy	15	7	7	3	4

Baseline characteristics

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Reporting group title

Secukinumab (AIN457) 75 mg s.c.

Reporting group description

Group 1- Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 150 mg s.c.

Reporting group description

Group 2 - Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 300 mg s.c.

Reporting group description

Group 3 - Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Placebo

Reporting group description

Placebo - rerandomized at Week 16 to receive secukinumab 150 mg s.c. or 300 mg s.c. from Week 16 (nonresponder) or Week 24 (responder).

Reporting group values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo	Total
Number of subjects	99	100	100	98	397
Age Categorical
Units: Participants
<=18 years	0	0	0	0	0
Between 18 and 65 years	93	94	90	87	364
>=65 years	6	6	10	11	33
Age continuous
Units: years
arithmetic mean (standard deviation)	48.6 ( 11.42 )	46.5 ( 11.72 )	46.9 ( 12.57 )	49.9 ( 12.53 )	-
Sex: Female, Male
Units: Participants
Female	52	45	49	59	205
Male	47	55	51	39	192
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	2	0	0	2
Asian	5	6	2	1	14
Native Hawaiian or Other Pacific Islander	1	1	0	0	2
Black or African American	0	0	1	0	1
White	90	90	96	94	370
More than one race	2	1	1	3	7
Unknown or Not Reported	1	0	0	0	1

End points

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Reporting group title

Secukinumab (AIN457) 75 mg s.c.

Reporting group description

Group 1- Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 150 mg s.c.

Reporting group description

Group 2 - Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 300 mg s.c.

Reporting group description

Group 3 - Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Placebo

Reporting group description

Placebo - rerandomized at Week 16 to receive secukinumab 150 mg s.c. or 300 mg s.c. from Week 16 (nonresponder) or Week 24 (responder).

Reporting group title

Secukinumab (AIN457) 75 mg s.c.

Reporting group description

Group 1- Secukinumab 75 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 150 mg s.c.

Reporting group description

Group 2 - Secukinumab 150 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Secukinumab (AIN457) 300 mg s.c.

Reporting group description

Group 3 - Secukinumab 300 mg at BSL, Weeks 1, 2, 3 and 4, followed by dosing every four weeks starting at Week 4 until up to Week 260.

Reporting group title

Placebo - AIN457 150 mg

Reporting group description

Placebo - rerandomized to AIN457 150 mg

Reporting group title

Placebo - AIN457 300 mg

Reporting group description

Placebo - rerandomized to AIN457 300 mg

Primary: Number of participants achieving American College of Rheumatology 20 (ACR20) response criteria

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End point title

Number of participants achieving American College of Rheumatology 20 (ACR20) response criteria

End point description

ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 20% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient’s assessment of RA pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire [HAQ-DI] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR20 response results at week 24 used non-responder imputation.

End point type

Primary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	99	100	100	98
Units: Participants	29	51	54	15

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

P-value

= 0.02

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.32

Confidence interval

level

95%

sides

2-sided

lower limit

1.14

upper limit

4.73

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

P-value

< 1

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6.52

Confidence interval

level

95%

sides

2-sided

lower limit

3.25

upper limit

13.08

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6.81

Confidence interval

level

95%

sides

2-sided

lower limit

3.42

upper limit

13.56

Secondary: Number of participants achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

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End point title

Number of participants achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

End point description

PASI is a combined assessment of a lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). The body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for a final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area * area score weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4). PASI 75 response was defined as participants achieving >= 75% improvement from baseline. The PASI75 response results at week 24 used non-responder imputation.

End point type

Secondary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	50	58	41	43
Units: Participants	14	28	26	7

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.165

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.07

Confidence interval

level

95%

sides

2-sided

lower limit

0.74

upper limit

5.81

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0006

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

5.7

Confidence interval

level

95%

sides

2-sided

lower limit

2.12

upper limit

15.34

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

9.48

Confidence interval

level

95%

sides

2-sided

lower limit

3.33

upper limit

Secondary: Number of participants achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

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End point title

Number of participants achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

End point description

PASI is a combined assessment of a lesion severity and affected area into a single score: 0 (no disease) to 72 (maximal disease). The body is divided into 4 areas for scoring (head, arms, trunk, legs; each area is scored by itself and scores are combined for a final PASI. For each area, percent of skin involved is estimated: 0 (0%) to 6 (90-100%), and severity is estimated by clinical signs, erythema, induration and desquamation; scale 0 (none) to 4 (maximum). Final PASI = sum of severity parameters for each area * area score weight of section (head: 0.1, arms: 0.2, body: 0.3, legs: 0.4). PASI 90 response was defined as participants achieving >= 90% improvement from baseline. The PASI90 response results at week 24 used non-responder imputation.

End point type

Secondary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	50	58	41	43
Units: Participants	6	19	20	4

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.6421

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

1.38

Confidence interval

level

95%

sides

2-sided

lower limit

0.36

upper limit

5.36

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

101

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0029

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

6.36

Confidence interval

level

95%

sides

2-sided

lower limit

1.89

upper limit

21.47

Odds Ratio (OR)

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0002

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

10.74

Confidence interval

level

95%

sides

2-sided

lower limit

3.13

upper limit

36.84

Secondary: Change from baseline in DAS28-CRP

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End point title

Change from baseline in DAS28-CRP

End point description

The DAS28 is a measure of disease activity in RA. The score is calculated by a mathematical formula, which includes the tender joint count(TJC) and swollen joint count (SJC) out of a total of 28 joints, the high-sensitivity C-reactive protein (hsCRP), and the subject's 'global assessment' of disease activity/general health (GH). The subject's global assessment/GH was indicated by a visual analogue scale of 100 mm where the participant marked a point on a 100 mm line between 0 and 100 (0 indicated very good and 100 indicated very bad). The following formula was used to calculate DAS28: DAS-CRP = 0.56*sqrt(TJC28) + 0.28*sqrt(SJC28) = 0.36*ln(CRP+1) + 0.014*GH = 0.96. A DAS28-CRP score > 5.1 implies active disease, <3.2 implies controlled disease and <2.6 implies remission. A negative change from baseline indicates improvement.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	87	91	93	32
Units: score on a scale
least squares mean (standard error)	-1.12 ( 0.111 )	-1.58 ( 0.109 )	-1.61 ( 0.110 )	-0.96 ( 0.149 )

Mean Difference

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

119

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3763

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-0.53

upper limit

0.2

Mean Difference

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

123

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0008

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.62

Confidence interval

level

95%

sides

2-sided

lower limit

-0.98

upper limit

-0.26

Mean Difference

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

125

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0004

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.65

Confidence interval

level

95%

sides

2-sided

lower limit

-1.02

upper limit

-0.29

Secondary: Change from baseline in SF36-Physical Component Score

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End point title

Change from baseline in SF36-Physical Component Score

End point description

The SF-36 is an instrument to measure health-related quality of life among healthy patients and patients with acute and chronic conditions Score range is from 0 (no problems) to 100 (unable to perform the activity) SF-36 is a 36 item questionnaire which measures Quality of Life across eight domains, which are both physically and emotionally based. Two overall summary scores, the Physical Component Summary (PCS) and Mental Component Summary (MCS) can be computed. In this study, SF-36 PCS is used.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	91	96	96	33
Units: Score on a scale
least squares mean (standard error)	4.38 ( 0.750 )	6.39 ( 0.734 )	7.25 ( 0.740 )	1.95 ( 0.974 )

Mean Difference

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

124

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0482

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

2.42

Confidence interval

level

95%

sides

2-sided

lower limit

0.02

upper limit

4.83

Mean Difference

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

4.44

Confidence interval

level

95%

sides

2-sided

lower limit

2.05

upper limit

6.83

Mean Difference

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

5.3

Confidence interval

level

95%

sides

2-sided

lower limit

2.91

upper limit

7.69

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

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End point title

Change From Baseline in Stanford Health Assessment Questionnaire Disability Index (HAQ-DI)

End point description

The HAQ-DI assesses a subject's level of functional ability and includes questions of fine movements of the upper extremity, locomotor activities of the lower extremity, and activities that involve both upper and lower extremities. There are 20 questions in 8 categories of functioning including dressing, rising, eating, walking, hygiene, reach, grip and usual activities. The stem of each item asks 'Over the past week, "are you able to..." perform a particular task'. Each item is scored on a 4 point scale from 0 - 3, representing normal, no difficulty (0), some difficulty (1), much difficulty (2) and unable to do (3). The disability index score is calculated as the mean of the available category scores, ranging from 0 to 3. A negative change from baseline indicates improvement.

End point type

Secondary

End point timeframe

Baseline, Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	89	95	95	33
Units: Scores on a scale
least squares mean (standard error)	-0.32 ( 0.050 )	-0.48 ( 0.049 )	-0.56 ( 0.050 )	-0.31 ( 0.060 )

Mean Difference

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

122

Analysis specification

Pre-specified

Analysis type

P-value

= 0.9195

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.01

Confidence interval

level

95%

sides

2-sided

lower limit

-0.16

upper limit

0.15

Mean Difference

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0278

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.17

Confidence interval

level

95%

sides

2-sided

lower limit

-0.32

upper limit

-0.02

Mean Difference

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

128

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0013

Method

Mixed models analysis

Parameter type

Mean difference (net)

Point estimate

-0.25

Confidence interval

level

95%

sides

2-sided

lower limit

-0.4

upper limit

-0.1

Secondary: Number of participants achieving American College of Rheumatology 50 (ACR50) response criteria

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End point title

Number of participants achieving American College of Rheumatology 50 (ACR50) response criteria

End point description

ACR20 response was defined as having a positive clinical response to treatment (individual improvement) in disease activity if the participant had at least 50% improvement in tender 68-joint count, swollen 66-joint count and at least 3 of the following 5 measures: patient’s assessment of RA pain, patient’s global assessment of disease activity, physician’s global assessment of disease activity, subject self-assessed disability (Health Assessment Questionnaire [HAQ-DI] score), and/or acute phase reactant (high sensitivity c-reactive protein (hsCRP) or erythrocyte sedimentation rate (ESR). The ACR50 response results at week 24 used non-responder imputation.

End point type

Secondary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	99	100	100	98
Units: Participants	18	35	35	7

Odds Ratio

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

197

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0245

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

2.91

Confidence interval

level

95%

sides

2-sided

lower limit

1.15

upper limit

7.36

Odds Ratio

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.15

Confidence interval

level

95%

sides

2-sided

lower limit

2.97

upper limit

17.22

Odds Ratio

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

198

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

7.54

Confidence interval

level

95%

sides

2-sided

lower limit

3.11

upper limit

18.25

Secondary: Number of participants with dactylitis in the subset of subjects who had dactylitis at baseline

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End point title

Number of participants with dactylitis in the subset of subjects who had dactylitis at baseline

End point description

Resolution of dactylitis was evaluated in the subset of patients who had disease activity at baseline. In this analysis, a lower percentage is desirable and resolution is defined as complete absence of the symptom.

End point type

Secondary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	33	32	46	27
Units: Participants	23	16	20	23

Odds Ratio

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.3149

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.51

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

1.91

Odds Ratio

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0056

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.16

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

0.58

Odds Ratio

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0021

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.14

Confidence interval

level

95%

sides

2-sided

lower limit

0.04

upper limit

0.5

Secondary: Number of participants with enthesitis in the subset of subjects who had enthesitis at baseline

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End point title

Number of participants with enthesitis in the subset of subjects who had enthesitis at baseline

End point description

Resolution of enthesitis was evaluated in the subset of patients who had disease activity at baseline. In this analysis, a lower percentage is desirable and resolution is defined as complete absence of the symptom.

End point type

Secondary

End point timeframe

Week 24

End point values	Secukinumab (AIN457) 75 mg s.c.	Secukinumab (AIN457) 150 mg s.c.	Secukinumab (AIN457) 300 mg s.c.	Placebo
Number of subjects analysed	68	64	56	65
Units: Participants	46	37	29	51

Odds Ratio

Comparison groups

Secukinumab (AIN457) 75 mg s.c. v Placebo

Number of subjects included in analysis

133

Analysis specification

Pre-specified

Analysis type

P-value

= 0.1678

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.58

Confidence interval

level

95%

sides

2-sided

lower limit

0.26

upper limit

1.26

Odds Ratio

Comparison groups

Secukinumab (AIN457) 300 mg s.c. v Placebo

Number of subjects included in analysis

121

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0025

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.29

Confidence interval

level

95%

sides

2-sided

lower limit

0.13

upper limit

0.65

Odds Ratio

Comparison groups

Secukinumab (AIN457) 150 mg s.c. v Placebo

Number of subjects included in analysis

129

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0108

Method

Regression, Logistic

Parameter type

Odds ratio (OR)

Point estimate

0.36

Confidence interval

level

95%

sides

2-sided

lower limit

0.17

upper limit

0.79

Adverse events

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Timeframe for reporting adverse events

Adverse events were reported from first dose of study Treatment until Last Patient Last Visit (LPLV), up to a maximum of 5 years.

Adverse event reporting additional description

Patients randomized to Placebo are reported under Placebo for AEs starting before switching to Secukinumab and under the Secukinumab arm for AEs starting after switching to Secukinumab. Under “# of deaths resulting from AEs” all those deaths, resulting from SAEs that are deemed to be causally related to treatment by the investigator are reported.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.1

Reporting group title

Any AIN457 75 mg

Reporting group description

Any AIN457 75 mg

Reporting group title

Any AIN457 300 mg

Reporting group description

Any AIN457 300 mg

Reporting group title

Placebo

Reporting group description

Placebo

Reporting group title

Any AIN457 150 mg

Reporting group description

Any AIN457 150 mg

Serious adverse events	Any AIN457 75 mg	Any AIN457 300 mg	Placebo	Any AIN457 150 mg
Total subjects affected by serious adverse events
subjects affected / exposed	17 / 99 (17.17%)	42 / 251 (16.73%)	3 / 98 (3.06%)	28 / 193 (14.51%)
number of deaths (all causes)	0	0	0	1
number of deaths resulting from adverse events	0	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
B-cell lymphoma
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Penile squamous cell carcinoma
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma
subjects affected / exposed	2 / 99 (2.02%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the tongue
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Throat cancer
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Thyroid cancer
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Arteriosclerosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral arterial occlusive disease
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vasculitis necrotising
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Social circumstances
Pregnancy of partner
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Cervical dysplasia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dysmenorrhoea
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Alcohol abuse
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Dependence
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Alcohol poisoning
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Animal bite
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	1 / 99 (1.01%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fractured ischium
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Fractured sacrum
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc injury
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Limb traumatic amputation
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post-traumatic neck syndrome
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Scar
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	1 / 99 (1.01%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery stenosis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical radiculopathy
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Headache
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegia
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Migraine
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Seizure
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Deafness neurosensory
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Vertigo
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Vision blurred
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Visual acuity reduced transiently
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Anal fistula
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Crohn's disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inflammatory bowel disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	1 / 98 (1.02%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar hernia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Bile duct obstruction
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic lesion
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hypertransaminasaemia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Liver disorder
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Photosensitivity reaction
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Psoriasis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Calculus urinary
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis reactive
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Arthrofibrosis
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	1 / 99 (1.01%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Patellofemoral pain syndrome
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pseudarthrosis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Abscess limb
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 99 (1.01%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Erysipelas
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	1 / 98 (1.02%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis norovirus
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Haematoma infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	1 / 98 (1.02%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis C
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infectious colitis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Infective exacerbation of chronic obstructive airways disease
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Kidney infection
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 99 (0.00%)	2 / 251 (0.80%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Periorbital abscess
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pharyngeal abscess
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	1 / 98 (1.02%)	1 / 193 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1
Septic shock
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	1 / 98 (1.02%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Subcutaneous abscess
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Viral infection
subjects affected / exposed	0 / 99 (0.00%)	0 / 251 (0.00%)	0 / 98 (0.00%)	2 / 193 (1.04%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	0 / 99 (0.00%)	1 / 251 (0.40%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Diabetes mellitus
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	1 / 99 (1.01%)	0 / 251 (0.00%)	0 / 98 (0.00%)	0 / 193 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Any AIN457 75 mg	Any AIN457 300 mg	Placebo	Any AIN457 150 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	63 / 99 (63.64%)	171 / 251 (68.13%)	39 / 98 (39.80%)	132 / 193 (68.39%)
Vascular disorders
Hypertension
subjects affected / exposed	6 / 99 (6.06%)	23 / 251 (9.16%)	3 / 98 (3.06%)	14 / 193 (7.25%)
occurrences all number	7	25	3	15
Nervous system disorders
Headache
subjects affected / exposed	6 / 99 (6.06%)	18 / 251 (7.17%)	5 / 98 (5.10%)	16 / 193 (8.29%)
occurrences all number	7	29	6	18
General disorders and administration site conditions
Fatigue
subjects affected / exposed	5 / 99 (5.05%)	11 / 251 (4.38%)	2 / 98 (2.04%)	6 / 193 (3.11%)
occurrences all number	5	12	2	6
Oedema peripheral
subjects affected / exposed	5 / 99 (5.05%)	4 / 251 (1.59%)	0 / 98 (0.00%)	3 / 193 (1.55%)
occurrences all number	5	5	0	3
Gastrointestinal disorders
Diarrhoea
subjects affected / exposed	11 / 99 (11.11%)	23 / 251 (9.16%)	3 / 98 (3.06%)	19 / 193 (9.84%)
occurrences all number	14	34	6	21
Nausea
subjects affected / exposed	7 / 99 (7.07%)	14 / 251 (5.58%)	4 / 98 (4.08%)	12 / 193 (6.22%)
occurrences all number	10	25	5	13
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	2 / 99 (2.02%)	12 / 251 (4.78%)	2 / 98 (2.04%)	13 / 193 (6.74%)
occurrences all number	2	15	2	14
Skin and subcutaneous tissue disorders
Psoriasis
subjects affected / exposed	7 / 99 (7.07%)	17 / 251 (6.77%)	4 / 98 (4.08%)	14 / 193 (7.25%)
occurrences all number	7	22	5	16
Rash
subjects affected / exposed	1 / 99 (1.01%)	13 / 251 (5.18%)	3 / 98 (3.06%)	8 / 193 (4.15%)
occurrences all number	1	15	3	11
Psychiatric disorders
Depression
subjects affected / exposed	5 / 99 (5.05%)	14 / 251 (5.58%)	2 / 98 (2.04%)	4 / 193 (2.07%)
occurrences all number	5	15	2	4
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	7 / 99 (7.07%)	25 / 251 (9.96%)	4 / 98 (4.08%)	24 / 193 (12.44%)
occurrences all number	13	49	5	37
Back pain
subjects affected / exposed	8 / 99 (8.08%)	21 / 251 (8.37%)	3 / 98 (3.06%)	11 / 193 (5.70%)
occurrences all number	8	23	3	12
Bursitis
subjects affected / exposed	5 / 99 (5.05%)	8 / 251 (3.19%)	0 / 98 (0.00%)	7 / 193 (3.63%)
occurrences all number	5	9	0	9
Musculoskeletal pain
subjects affected / exposed	2 / 99 (2.02%)	12 / 251 (4.78%)	2 / 98 (2.04%)	12 / 193 (6.22%)
occurrences all number	3	15	2	19
Pain in extremity
subjects affected / exposed	5 / 99 (5.05%)	11 / 251 (4.38%)	3 / 98 (3.06%)	5 / 193 (2.59%)
occurrences all number	7	12	4	7
Psoriatic arthropathy
subjects affected / exposed	12 / 99 (12.12%)	23 / 251 (9.16%)	2 / 98 (2.04%)	24 / 193 (12.44%)
occurrences all number	12	27	2	32
Infections and infestations
Bronchitis
subjects affected / exposed	7 / 99 (7.07%)	19 / 251 (7.57%)	2 / 98 (2.04%)	13 / 193 (6.74%)
occurrences all number	9	25	2	18
Influenza
subjects affected / exposed	3 / 99 (3.03%)	14 / 251 (5.58%)	0 / 98 (0.00%)	10 / 193 (5.18%)
occurrences all number	3	16	0	12
Nasopharyngitis
subjects affected / exposed	23 / 99 (23.23%)	47 / 251 (18.73%)	8 / 98 (8.16%)	41 / 193 (21.24%)
occurrences all number	32	104	12	68
Oral herpes
subjects affected / exposed	5 / 99 (5.05%)	8 / 251 (3.19%)	2 / 98 (2.04%)	2 / 193 (1.04%)
occurrences all number	6	15	2	9
Pharyngitis
subjects affected / exposed	1 / 99 (1.01%)	15 / 251 (5.98%)	0 / 98 (0.00%)	6 / 193 (3.11%)
occurrences all number	1	26	0	8
Respiratory tract infection
subjects affected / exposed	5 / 99 (5.05%)	7 / 251 (2.79%)	0 / 98 (0.00%)	5 / 193 (2.59%)
occurrences all number	6	8	0	11
Rhinitis
subjects affected / exposed	5 / 99 (5.05%)	9 / 251 (3.59%)	0 / 98 (0.00%)	6 / 193 (3.11%)
occurrences all number	7	10	0	7
Sinusitis
subjects affected / exposed	6 / 99 (6.06%)	30 / 251 (11.95%)	1 / 98 (1.02%)	16 / 193 (8.29%)
occurrences all number	10	47	1	27
Upper respiratory tract infection
subjects affected / exposed	23 / 99 (23.23%)	58 / 251 (23.11%)	7 / 98 (7.14%)	40 / 193 (20.73%)
occurrences all number	37	97	7	57
Urinary tract infection
subjects affected / exposed	8 / 99 (8.08%)	19 / 251 (7.57%)	4 / 98 (4.08%)	16 / 193 (8.29%)
occurrences all number	10	31	4	23

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Were there any global substantial amendments to the protocol? Yes

25 Feb 2014

To expand the statistical hierarchy (primary plus ranked secondary variables) to include endpoints which are relevant to determining the overall therapeutic value of a therapy for PsA. These endpoints include but are not limited to PASI75, PASI90, DAS28-CRP, HAQDI, SF-36, dactylitis and enthesitis.

21 Oct 2015

To allow dose escalation of secukinumab administered s.c. every 4 weeks from 75 mg to 150 mg or 300 mg, and from 150 mg to 300 mg.

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

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Number of participants achieving American College of Rheumatology 20 (ACR20) response criteria

Primary: Number of participants achieving American College of Rheumatology 20 (ACR20) response criteria

Secondary: Number of participants achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

Secondary: Number of participants achieving a PASI75 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

Secondary: Number of participants achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

Secondary: Number of participants achieving a PASI90 response in the subgroup of subjects who have ≥3% skin involvement with psoriasis

Secondary: Change from baseline in DAS28-CRP

Secondary: Change from baseline in DAS28-CRP

Secondary: Change from baseline in SF36-Physical Component Score

Secondary: Change from baseline in SF36-Physical Component Score

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

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

Secondary: Number of participants achieving American College of Rheumatology 50 (ACR50) response criteria

Secondary: Number of participants achieving American College of Rheumatology 50 (ACR50) response criteria

Secondary: Number of participants with dactylitis in the subset of subjects who had dactylitis at baseline

Secondary: Number of participants with dactylitis in the subset of subjects who had dactylitis at baseline

Secondary: Number of participants with enthesitis in the subset of subjects who had enthesitis at baseline

Secondary: Number of participants with enthesitis in the subset of subjects who had enthesitis at baseline

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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