Study to Examine the Clinical Efficacy and the Nonsteroidal Anti-inflammatory Drug (NSAID)-Sparing Effect of Secukinumab Over 16 Weeks in Patients With Ankylosing Spondylitis (ASTRUM)

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ClinicalTrials.gov Identifier: NCT02763046

Recruitment Status : Completed

First Posted : May 5, 2016

Results First Posted : October 9, 2020

Last Update Posted : October 9, 2020

Sponsor:

Information provided by (Responsible Party):

Novartis ( Novartis Pharmaceuticals )

Study Type	Interventional
Study Design	Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Triple (Participant, Care Provider, Investigator); Primary Purpose: Treatment
Condition	Ankylosing Spondylitis
Interventions	Drug: Secukinumab (AIN457) 150 mg s.c. Drug: Placebo - Secukinumab (AIN457) 150 mg s.c.
Enrollment	211

Participant Flow

Recruitment Details	Participants took part in 40 investigative sites in Germany.
Pre-assignment Details	Participants were randomized 1:1:1 to one of the following treatment groups: secukinumab 150 mg s.c. with delayed NSAID tapering, secukinumab 150 mg s.c. with early NSAID tapering and placebo.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo
Arm/Group Description	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...
Arm/Group Description	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.
Period Title: Overall Study
Started	71	70	70
Completed	62	65	62
Not Completed	9	5	8
Reason Not Completed
Adverse Event	5	4	0
Lack of Efficacy	1	1	3
Physician Decision	1	0	1
Subject/guardian decision	2	0	4

Baseline Characteristics

Arm/Group Title		Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo	Total
Arm/Group Description		Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...	Total of all reporting groups
Arm/Group Description		Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.	Total of all reporting groups
Overall Number of Baseline Participants		71	70	70	211
Baseline Analysis Population Description		[Not Specified]
Baseline Analysis Population Description		[Not Specified]
Age, Continuous Mean (Standard Deviation) Unit of measure: Years
	Number Analyzed	71 participants	70 participants	70 participants	211 participants
		46.2 (13.36)	44.1 (11.02)	45.4 (12.55)	45.2 (12.32)
Sex: Female, Male Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	71 participants	70 participants	70 participants	211 participants
	Female	30 42.3%	28 40.0%	31 44.3%	89 42.2%
	Male	41 57.7%	42 60.0%	39 55.7%	122 57.8%
Race/Ethnicity, Customized Measure Type: Count of Participants Unit of measure: Participants
	Number Analyzed	71 participants	70 participants	70 participants	211 participants
	Caucasian	69 97.2%	67 95.7%	68 97.1%	204 96.7%
	Black	1 1.4%	0 0.0%	0 0.0%	1 0.5%
	Asian	0 0.0%	2 2.9%	1 1.4%	3 1.4%
	Other	1 1.4%	1 1.4%	1 1.4%	3 1.4%

Outcome Measures

1.Primary Outcome


Title	Proportion of Patients Who Achieved ASAS20 Response in the Pooled Secukinumab Group Compared With the Placebo Group at Week 12
Description	ASAS (Assessment of Spon...
Description	ASAS (Assessment of SpondyloArthritis International Society criteria) 20 response is defined as an improvement from baseline of ≥20% and ≥1 unit on a scale of 0-10 in at least three of the four ASAS main domains and no worsening of ≥20% and ≥1 unit on a scale of 0-10 in the remaining domain. The four main ASAS domains are: Patient's global assessment of disease activity, back pain, function represented by ability to perform specific tasks (from Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) and inflammation represented by mean duration and severity of morning stiffness. Non-responder imputation was applied for missing data.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

Full analysis set (FAS) comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Pooled	Placebo
Arm/Group Description:	The 2 secukinumab arms (delayed NSA...	Placebo s.c. at Week 0, 1, 2, 3, 4,...
Arm/Group Description:	The 2 secukinumab arms (delayed NSAID tapering and early NSAID tapering) pooled.	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.
Overall Number of Participants Analyzed	141	70
Measure Type: Count of Participants Unit of Measure: Participants
	72 51.1%	31 44.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Pooled, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3512
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.32
	Confidence Interval	(2-Sided) 95% 0.74 to 2.36
	Estimation Comments	[Not Specified]

2.Secondary Outcome


Title	Proportion of Patients Who Achieved ASAS20 Response in Each Secukinumab Group (Delayed NSAID Tapering and Early NSAID Tapering) Compared With the Placebo Group
Description	ASAS (Assessment of Spon...
Description	ASAS (Assessment of SpondyloArthritis International Society criteria) 20 response is defined as an improvement from baseline of ≥20% and ≥1 unit on a scale of 0-10 in at least three of the four ASAS main domains and no worsening of ≥20% and ≥1 unit on a scale of 0-10 in the remaining domain. The four main ASAS domains are: Patient's global assessment of disease activity, back pain, function represented by ability to perform specific tasks (from Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]) and inflammation represented by mean duration and severity of morning stiffness. Non-responder imputation was applied for missing data.
Time Frame	Baseline, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

FAS comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo
Arm/Group Description:	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...
Arm/Group Description:	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.
Overall Number of Participants Analyzed	71	70	70
Measure Type: Count of Participants Unit of Measure: Participants
Week 12	37 52.1%	35 50.0%	31 44.3%
Week 16	40 56.3%	35 50.0%	29 41.4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4010
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.33
	Confidence Interval	(2-Sided) 95% 0.68 to 2.60
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.4382
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.30
	Confidence Interval	(2-Sided) 95% 0.67 to 2.55
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0934
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.78
	Confidence Interval	(2-Sided) 95% 0.91 to 3.50
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2619
	Comments	[Not Specified]
	Method	Regression, Logistic
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	Odds Ratio (OR)
	Estimated Value	1.47
	Confidence Interval	(2-Sided) 95% 0.75 to 2.90
	Estimation Comments	[Not Specified]

3.Secondary Outcome


Title	Mean Change From Baseline in ASAS-NSAID Score at Week 12
Description	ASAS-NSAID score is used...
Description	ASAS-NSAID score is used to present the NSAID (nonsteroidal anti-inflammatory drug) intake by considering the type of NSAID, the total dose and the number of days taking NSAID during a period of interest (PI). For the NSAID equivalence scoring system, "no NSAID intake" was set to a score value of 0, and the reference dose of 150 mg/day diclofenac was set to a score value of 100. The Daily diclofenac-equivalent dose score was derived by converting each daily dose of NSAID to a percentage dose equivalent of 150 mg diclofenac. ASAS-NSAID score = (equivalent NSAID score) x (days of intake during PI) x (days per week)/(PI in days). A negative change from baseline indicates less NSAID consumption.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

FAS comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo	Secukinumab - Pooled
Arm/Group Description:	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...	The 2 secukinumab arms (delayed NSA...
Arm/Group Description:	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.	The 2 secukinumab arms (delayed NSAID tapering and early NSAID tapering) pooled.
Overall Number of Participants Analyzed	71	70	70	141
Mean (Standard Deviation) Unit of Measure: Score on scale
	-44.9 (47.32)	-40.3 (71.48)	-31.5 (36.54)	-42.6 (60.53)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Secukinumab - Pooled
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0997
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS (least square) Mean
	Estimated Value	-10.29
	Confidence Interval	(2-Sided) 95% -22.55 to 1.96
	Parameter Dispersion	Type: Standard Error of the Mean Value: 6.25
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0888
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-12.30
	Confidence Interval	(2-Sided) 95% -26.47 to 1.87
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.23
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2484
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-8.29
	Confidence Interval	(2-Sided) 95% -22.36 to 5.79
	Parameter Dispersion	Type: Standard Error of the Mean Value: 7.18
	Estimation Comments	[Not Specified]

4.Secondary Outcome


Title	Mean Change From Baseline in ASAS-NSAID Score in Each Secukinumab Group After 12 Weeks of Exposure (at Week 12 in the Secukinumab-delayed NSAID Tapering Group and at Week 16 in the Secukinumab-early NSAID Tapering Group)
Description	ASAS-NSAID score is used...
Description	ASAS-NSAID score is used to present the NSAID (nonsteroidal anti-inflammatory drug) intake by considering the type of NSAID, the total dose and the number of days taking NSAID during a period of interest (PI). For the NSAID equivalence scoring system, "no NSAID intake" was set to a score value of 0, and the reference dose of 150 mg/day diclofenac was set to a score value of 100. The Daily diclofenac-equivalent dose score was derived by converting each daily dose of NSAID to a percentage dose equivalent of 150 mg diclofenac. ASAS-NSAID score = (equivalent NSAID score) x (days of intake during PI) x (days per week)/(PI in days). A negative change from baseline indicates less NSAID consumption. For this endpoint the analysis was performed after 12 weeks of exposure to secukinumab which was achieved at Week 12 in the secukinumab delayed NSAID tapering group but at Week 16 in the secukinumab early NSAID tapering group.
Time Frame	Baseline, Week 12 (delayed NSAID tapering), Week 16 (early NSAID tapering)

Outcome Measure Data

Analysis Population Description

FAS comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering
Arm/Group Description:	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...
Arm/Group Description:	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).
Overall Number of Participants Analyzed	71	70
Mean (Standard Deviation) Unit of Measure: Score on scale
	-44.9 (47.32)	-42.5 (68.62)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Secukinumab - Early NSAID Tapering
	Comments	delayed tapering (W12) vs early tapering (W16)
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.7735
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-2.06
	Confidence Interval	(2-Sided) 95% -16.11 to 11.98
	Estimation Comments	[Not Specified]

5.Secondary Outcome


Title	Mean Change From Baseline in the BASDAI Total Score
Description	The BASDAI (Bath Ankylos...
Description	The BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) is a participant-reported assessment consisting of 6 questions that relate to 5 major symptoms relevant to ankylosing spondylitis: 1) Fatigue, 2) Spinal pain, 3) Peripheral arthritis, 4) Enthesitis, 5) Intensity, and 6) Duration of morning stiffness. Participants need to score each item with a score from 0 to 10 (captured as a continuous visual analog scale). Total score is obtained from the average of symptom scores ranging 0 (no problem) to 10 (worst problem), with a higher score indicating more severe symptoms. A negative change from baseline in the total 0-10 BASDAI score indicates improvement.
Time Frame	Baseline, Week 12, Week 16

Outcome Measure Data

Analysis Population Description

FAS comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo	Secukinumab - Pooled
Arm/Group Description:	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...	The 2 secukinumab arms (delayed NSA...
Arm/Group Description:	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.	The 2 secukinumab arms (delayed NSAID tapering and early NSAID tapering) pooled.
Overall Number of Participants Analyzed	71	70	70	141
Mean (Standard Deviation) Unit of Measure: Score on scale
Week 12	-2.1 (2.16)	-2.0 (2.10)	-1.8 (2.00)	-2.1 (2.12)
Week 16	-2.3 (1.90)	-2.0 (1.96)	-1.7 (1.96)	-2.2 (1.93)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Secukinumab - Pooled
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1926
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.39
	Confidence Interval	(2-Sided) 95% -0.99 to 0.20
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.30
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.1914
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.46
	Confidence Interval	(2-Sided) 95% -1.14 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.35
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	Week 12
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.3397
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.33
	Confidence Interval	(2-Sided) 95% -1.01 to 0.35
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.34
	Estimation Comments	[Not Specified]

Statistical Analysis 4

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.0384
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.68
	Confidence Interval	(2-Sided) 95% -1.33 to -0.04
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.33
	Estimation Comments	[Not Specified]

Statistical Analysis 5

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	Week 16
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2116
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.41
	Confidence Interval	(2-Sided) 95% -1.05 to 0.23
	Parameter Dispersion	Type: Standard Error of the Mean Value: 0.33
	Estimation Comments	[Not Specified]

6.Secondary Outcome


Title	Mean Change From Baseline in Health-related Quality of Life as Measured by the Short Form-36 Health Survey (SF-36) Physical Component Summary (PCS) Score
Description	The Short Form-36 Health Survey (SF-36) measures the impact of disease...
Description	The Short Form-36 Health Survey (SF-36) measures the impact of disease on overall quality of life by assessing 1) limitations in physical functioning due to health problems; 2) limitations in usual role because of physical health problems; 3) bodily pain; 4) general health perceptions; 5) vitality; 6) limitations in social functioning because of physical or emotional problems; 7) limitations in usual role due to emotional problems; and 8) general mental health. Items 1-4 comprise the physical component of the SF-36 (SF-36 PCS) that is evaluated in this study. Scores on each item 1-4 were summed and averaged (range = 0-100 with higher scores indicating better levels of function and/or better health). A positive change from Baseline indicates improvement.
Time Frame	Baseline, Week 12

Outcome Measure Data

Analysis Population Description

FAS comprising all subjects from the randomized set to whom study treatment was assigned.


Arm/Group Title	Secukinumab - Delayed NSAID Tapering	Secukinumab - Early NSAID Tapering	Placebo	Secukinumab - Pooled
Arm/Group Description:	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...	The 2 secukinumab arms (delayed NSA...
Arm/Group Description:	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering).	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering).	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4.	The 2 secukinumab arms (delayed NSAID tapering and early NSAID tapering) pooled.
Overall Number of Participants Analyzed	71	70	70	141
Mean (Standard Deviation) Unit of Measure: Score on scale
	4.8 (7.03)	6.1 (6.92)	4.8 (7.43)	5.5 (6.98)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, Secukinumab - Pooled
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.5384
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	0.63
	Confidence Interval	(2-Sided) 95% -1.38 to 2.63
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.02
	Estimation Comments	[Not Specified]

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Delayed NSAID Tapering, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.9251
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	-0.11
	Confidence Interval	(2-Sided) 95% -2.43 to 2.21
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.18
	Estimation Comments	[Not Specified]

Statistical Analysis 3

Statistical Analysis Overview	Comparison Group Selection	Secukinumab - Early NSAID Tapering, Placebo
	Comments	[Not Specified]
	Type of Statistical Test	Superiority
	Comments	[Not Specified]

Statistical Test of Hypothesis	P-Value	0.2432
	Comments	[Not Specified]
	Method	Mixed Model for Repeated Measures (MMRM)
	Comments	[Not Specified]

Method of Estimation	Estimation Parameter	LS Mean
	Estimated Value	1.36
	Confidence Interval	(2-Sided) 95% -0.93 to 3.66
	Parameter Dispersion	Type: Standard Error of the Mean Value: 1.16
	Estimation Comments	[Not Specified]

Adverse Events

Time Frame	Adverse events were collected from first dose of study treatment until end of study treatment plus 4 weeks post-treatment (median duration of 24 weeks).
Adverse Event Reporting Description	Any signs or symptoms that occurs from first study drug treatment until 30 days after the last study drug treatment. Adverse events were analyzed by treatment period, i.e., Treatment Period 1 from first study drug administration at baseline through Week 16 (concretely: until the day before the injection of study drug scheduled at visit Week 16) and Treatment Period 2 (from the day of injection at visit Week 16 onwards until study end).

Arm/Group Title	Secukinumab - Delayed NSAID Tapering - Treatment Period 1	Secukinumab - Early NSAID Tapering - Treatment Period 1	Placebo - Treatment Period 1	Secukinumab - Delayed NSAID Tapering - Treatment Period 2	Secukinumab - Early NSAID Tapering - Treatment Period 2	Placebo - Treatment Period 2
Arm/Group Description	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...	Induction with secukinumab 150 mg s...	Placebo at weeks 0, 1, 2, 3 to main...	Placebo s.c. at Week 0, 1, 2, 3, 4,...
Arm/Group Description	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering). Treatment Period 1: from first study drug administration at baseline through Week 16 (concretely: until the day before the injection of study drug scheduled at visit Week 16). This corresponds to the placebo-controlled period of the study.	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering). Treatment Period 1: from first study drug administration at baseline through Week 16 (concretely: until the day before the injection of study drug scheduled at visit Week 16). This corresponds to the placebo-controlled period of the study.	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4. Treatment Period 1: from first study drug administration at baseline through Week 16 (concretely: until the day before the injection of study drug scheduled at visit Week 16). This corresponds to the placebo-controlled period of the study.	Induction with secukinumab 150 mg s.c. once per week (Week 0, 1, 2, 3 and 4) followed by maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 8, 12, 16 and 20), with intermittent placebo injections at Week 5, 6, 7, 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (delayed tapering). Treatment Period 2: from the day of injection at visit Week 16 onwards until study end.	Placebo at weeks 0, 1, 2, 3 to maintain the blind; followed by induction with secukinumab 150 mg s.c. once per week (Week 4, 5, 6, 7, 8) and maintenance with secukinumab 150 mg s.c. every 4 weeks (Week 12, 16 and 20), with intermittent placebo injections at Week 17, 18 and 19 to maintain the blind. NSAID tapering allowed from Week 4 (early tapering). Treatment Period 2: from the day of injection at visit Week 16 onwards until study end.	Placebo s.c. at Week 0, 1, 2, 3, 4, 5, 6, 7, 8 and 12. After the Week 16 assessments of the secondary endpoint had been performed, these patients received weekly doses of secukinumab 150 mg s.c. (Week 16, 17, 18, 19 and 20). NSAID tapering allowed from Week 4. Treatment Period 2: from the day of injection at visit Week 16 onwards until study end.
All-Cause Mortality
	Secukinumab - Delayed NSAID Tapering - Treatment Period 1	Secukinumab - Early NSAID Tapering - Treatment Period 1	Placebo - Treatment Period 1	Secukinumab - Delayed NSAID Tapering - Treatment Period 2	Secukinumab - Early NSAID Tapering - Treatment Period 2	Placebo - Treatment Period 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Serious Adverse Events Serious Adverse Events
	Secukinumab - Delayed NSAID Tapering - Treatment Period 1	Secukinumab - Early NSAID Tapering - Treatment Period 1	Placebo - Treatment Period 1	Secukinumab - Delayed NSAID Tapering - Treatment Period 2	Secukinumab - Early NSAID Tapering - Treatment Period 2	Placebo - Treatment Period 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	4/71 (5.63%)	3/70 (4.29%)	1/70 (1.43%)	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)
Eye disorders
Iridocyclitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Gastrointestinal disorders
Abdominal hernia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Abdominal pain ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Colitis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Crohn's disease ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastritis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Inguinal hernia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Oesophageal ulcer ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Infections and infestations
Erysipelas ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Renal and urinary disorders
Nephrolithiasis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Reproductive system and breast disorders
Vaginal cyst ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Skin and subcutaneous tissue disorders
Psoriasis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
1 Term from vocabulary, MedDRA (22.1) † Indicates events were collected by systematic assessment
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Secukinumab - Delayed NSAID Tapering - Treatment Period 1	Secukinumab - Early NSAID Tapering - Treatment Period 1	Placebo - Treatment Period 1	Secukinumab - Delayed NSAID Tapering - Treatment Period 2	Secukinumab - Early NSAID Tapering - Treatment Period 2	Placebo - Treatment Period 2
	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)	Affected / at Risk (%)
Total	53/71 (74.65%)	56/70 (80.00%)	55/70 (78.57%)	25/71 (35.21%)	23/70 (32.86%)	22/70 (31.43%)
Blood and lymphatic system disorders
Anaemia ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Iron deficiency anaemia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Leukopenia ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Lymph node pain ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Lymphopenia ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Monoclonal B-cell lymphocytosis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Monocytosis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Neutrophilia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Cardiac disorders
Bradycardia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Coronary artery disease ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Palpitations ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Tachycardia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Ear and labyrinth disorders
Ear pain ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Tinnitus ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Vertigo ^† 1	1/71 (1.41%)	0/70 (0.00%)	3/70 (4.29%)	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)
Endocrine disorders
Hyperprolactinaemia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hypothyroidism ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Eye disorders
Diplopia ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Dry eye ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Eye irritation ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Eye pain ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Iritis ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Macular degeneration ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Presbyopia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Uveitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Visual impairment ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastrointestinal disorders
Abdominal pain ^† 1	3/71 (4.23%)	3/70 (4.29%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Abdominal pain lower ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Abdominal pain upper ^† 1	3/71 (4.23%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Aphthous ulcer ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Colitis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Constipation ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Diarrhoea ^† 1	3/71 (4.23%)	3/70 (4.29%)	3/70 (4.29%)	1/71 (1.41%)	1/70 (1.43%)	3/70 (4.29%)
Diarrhoea haemorrhagic ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Dry mouth ^† 1	0/71 (0.00%)	2/70 (2.86%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Dyspepsia ^† 1	0/71 (0.00%)	3/70 (4.29%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Dysphagia ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Enteritis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Frequent bowel movements ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastritis ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastrooesophageal reflux disease ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gingival discomfort ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Haematochezia ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hiatus hernia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Inguinal hernia ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Nausea ^† 1	2/71 (2.82%)	2/70 (2.86%)	5/70 (7.14%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Stomatitis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Toothache ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
General disorders
Discomfort ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Fatigue ^† 1	0/71 (0.00%)	1/70 (1.43%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Feeling hot ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Impaired healing ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Influenza like illness ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Injection site pruritus ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Injection site urticaria ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Non-cardiac chest pain ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Oedema peripheral ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Peripheral swelling ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Polyp ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Pyrexia ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Thirst ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hepatobiliary disorders
Cholelithiasis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hepatic steatosis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Immune system disorders
Allergy to arthropod bite ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Seasonal allergy ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Infections and infestations
Bacterial vaginosis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Bronchitis ^† 1	5/71 (7.04%)	2/70 (2.86%)	3/70 (4.29%)	2/71 (2.82%)	1/70 (1.43%)	1/70 (1.43%)
Candida infection ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Conjunctivitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	2/71 (2.82%)	0/70 (0.00%)	0/70 (0.00%)
Cystitis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Epstein-Barr virus infection ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Erysipelas ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Folliculitis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Fungal infection ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Fungal skin infection ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Furuncle ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastroenteritis ^† 1	2/71 (2.82%)	4/70 (5.71%)	3/70 (4.29%)	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)
Gastroenteritis viral ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Gastrointestinal infection ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gastrointestinal viral infection ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Herpes simplex ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Infected bite ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Influenza ^† 1	1/71 (1.41%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Laryngitis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Lower respiratory tract infection ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Lyme disease ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Nasopharyngitis ^† 1	6/71 (8.45%)	13/70 (18.57%)	14/70 (20.00%)	7/71 (9.86%)	5/70 (7.14%)	3/70 (4.29%)
Oesophageal candidiasis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Onychomycosis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Oral candidiasis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Oral herpes ^† 1	2/71 (2.82%)	2/70 (2.86%)	0/70 (0.00%)	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)
Otitis externa ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Otitis media ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Pharyngitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Pneumonia ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Pulpitis dental ^† 1	1/71 (1.41%)	2/70 (2.86%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Respiratory tract infection ^† 1	2/71 (2.82%)	4/70 (5.71%)	3/70 (4.29%)	1/71 (1.41%)	1/70 (1.43%)	3/70 (4.29%)
Respiratory tract infection viral ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Rhinitis ^† 1	4/71 (5.63%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Sinusitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Subcutaneous abscess ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Trichomoniasis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Upper respiratory tract infection ^† 1	1/71 (1.41%)	3/70 (4.29%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	2/70 (2.86%)
Urinary tract infection ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Uterine infection ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Injury, poisoning and procedural complications
Animal bite ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Bone contusion ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Contusion ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Fall ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Hand fracture ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Joint dislocation ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Ligament rupture ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Ligament sprain ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Limb injury ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Muscle injury ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Muscle strain ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Overdose ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Post-traumatic neck syndrome ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)
Reactive gastropathy ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Road traffic accident ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)
Spinal column injury ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Wound ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Investigations
Alanine aminotransferase increased ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Aspartate aminotransferase increased ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Blood glucose increased ^† 1	2/71 (2.82%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Blood pressure decreased ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Blood pressure increased ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Gamma-glutamyltransferase increased ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hepatic enzyme increased ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Laboratory test abnormal ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Liver function test increased ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Lymphocyte count decreased ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Red blood cell sedimentation rate increased ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Transaminases increased ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Weight decreased ^† 1	2/71 (2.82%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
White blood cell count decreased ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
White blood cell count increased ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Metabolism and nutrition disorders
Decreased appetite ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Diabetes mellitus ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hypercholesterolaemia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Pseudohyperkalaemia ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Pseudohypoglycaemia ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Musculoskeletal and connective tissue disorders
Ankylosing spondylitis ^† 1	3/71 (4.23%)	1/70 (1.43%)	6/70 (8.57%)	2/71 (2.82%)	0/70 (0.00%)	1/70 (1.43%)
Arthralgia ^† 1	2/71 (2.82%)	2/70 (2.86%)	2/70 (2.86%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Arthritis ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Back pain ^† 1	4/71 (5.63%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Bursitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Joint swelling ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Muscle spasms ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Muscle tightness ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Musculoskeletal chest pain ^† 1	0/71 (0.00%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Musculoskeletal pain ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Myalgia ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Osteoarthritis ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Pain in extremity ^† 1	1/71 (1.41%)	2/70 (2.86%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Rheumatic fever ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Sacroiliitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Spinal osteoarthritis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Spinal pain ^† 1	0/71 (0.00%)	1/70 (1.43%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Spondylitis ^† 1	0/71 (0.00%)	1/70 (1.43%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Spondyloarthropathy ^† 1	1/71 (1.41%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Spondylolisthesis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Synovial cyst ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Tendon disorder ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Tendon pain ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Tendonitis ^† 1	0/71 (0.00%)	1/70 (1.43%)	1/70 (1.43%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Tenosynovitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Nervous system disorders
Ageusia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Autonomic nervous system imbalance ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Cervicobrachial syndrome ^† 1	1/71 (1.41%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Disturbance in attention ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Dizziness ^† 1	0/71 (0.00%)	2/70 (2.86%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Dysaesthesia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Dysgeusia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Headache ^† 1	12/71 (16.90%)	10/70 (14.29%)	6/70 (8.57%)	4/71 (5.63%)	3/70 (4.29%)	1/70 (1.43%)
Intercostal neuralgia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Migraine ^† 1	1/71 (1.41%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Nerve compression ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Paraesthesia ^† 1	2/71 (2.82%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Paresis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Presyncope ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Sciatica ^† 1	1/71 (1.41%)	1/70 (1.43%)	1/70 (1.43%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Tension headache ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Tremor ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Psychiatric disorders
Apathy ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Depression ^† 1	1/71 (1.41%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Insomnia ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Nervousness ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Restlessness ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Sleep disorder ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Renal and urinary disorders
Dysuria ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Haematuria ^† 1	1/71 (1.41%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Proteinuria ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Renal failure ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Urinary incontinence ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Reproductive system and breast disorders
Dysmenorrhoea ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Menorrhagia ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Uterine pain ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Vaginal haemorrhage ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Vulvovaginal pain ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Respiratory, thoracic and mediastinal disorders
Asthma ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Chronic obstructive pulmonary disease ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Cough ^† 1	2/71 (2.82%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	3/70 (4.29%)	0/70 (0.00%)
Dyspnoea exertional ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Nasal congestion ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Oropharyngeal pain ^† 1	0/71 (0.00%)	2/70 (2.86%)	1/70 (1.43%)	0/71 (0.00%)	3/70 (4.29%)	0/70 (0.00%)
Rhinorrhoea ^† 1	0/71 (0.00%)	2/70 (2.86%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Skin and subcutaneous tissue disorders
Angioedema ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Dermatitis ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Dyshidrotic eczema ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Eczema ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Eczema asteatotic ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Erythema ^† 1	1/71 (1.41%)	0/70 (0.00%)	2/70 (2.86%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Guttate psoriasis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hyperhidrosis ^† 1	0/71 (0.00%)	2/70 (2.86%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Night sweats ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Palmoplantar pustulosis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Photosensitivity reaction ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Pruritus ^† 1	1/71 (1.41%)	1/70 (1.43%)	3/70 (4.29%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Psoriasis ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Rash ^† 1	2/71 (2.82%)	1/70 (1.43%)	3/70 (4.29%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Rash maculo-papular ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Seborrhoea ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Skin exfoliation ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Skin fissures ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Skin irritation ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Solar dermatitis ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)
Xeroderma ^† 1	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)
Vascular disorders
Circulatory collapse ^† 1	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Haematoma ^† 1	1/71 (1.41%)	0/70 (0.00%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
Hypertension ^† 1	4/71 (5.63%)	3/70 (4.29%)	4/70 (5.71%)	0/71 (0.00%)	0/70 (0.00%)	1/70 (1.43%)
Hypotension ^† 1	0/71 (0.00%)	1/70 (1.43%)	0/70 (0.00%)	0/71 (0.00%)	0/70 (0.00%)	0/70 (0.00%)
1 Term from vocabulary, MedDRA (22.1) † Indicates events were collected by systematic assessment

Limitations and Caveats

[Not Specified]

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Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

The terms and conditions of Novartis' agreements with its investigators may vary. Novartis does not prohibit any investigator from publishing. Any publications from a single site are postponed until the publication of the pooled data (ie, data from all sites) in the clinical trial.

Results Point of Contact

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Name/Title:	Study Director
Organization:	Novartis Pharmaceuticals
Phone:	862-778-8300
EMail:	Novartis.email@novartis.com

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Responsible Party:	Novartis ( Novartis Pharmaceuticals )
ClinicalTrials.gov Identifier:	NCT02763046
Other Study ID Numbers:	CAIN457FDE03 2015-004575-74 ( EudraCT Number )
First Submitted:	May 3, 2016
First Posted:	May 5, 2016
Results First Submitted:	September 16, 2020
Results First Posted:	October 9, 2020
Last Update Posted:	October 9, 2020

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