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Clinical Trial Results:
A Phase 3 Randomized, Double-blind, Multi-dose, Placebo and Naproxen-Controlled Study to Evaluate the Efficacy and Safety of Fasinumab in Patients with Pain Due to Osteoarthritis of the Knee or Hip

Summary
EudraCT number	2016-005020-29
Trial protocol	BG LT GB DK PL HU ES RO
Global end of trial date	27 Aug 2021

Results information
Results version number	v1(current)
This version publication date	10 Sep 2022
First version publication date	10 Sep 2022
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

R475-OA-1611

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Regeneron Pharmaceuticals, Inc.

Sponsor organisation address

777 Old Saw Mill River Road, Tarrytown, NY, United States, 10591

Public contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.com

Scientific contact

Clinical Trials Administrator, Regeneron Pharmaceuticals, Inc., 001 844-734-6643, clinicaltrials@regeneron.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

27 Aug 2021

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

27 Aug 2021

Was the trial ended prematurely?

Main objective of the trial

The primary objective was to evaluate the efficacy of fasinumab compared with placebo, when administered for up to 16 weeks in participants with pain due to osteoarthritis (OA) of the knee or hip.

Protection of trial subjects

It is the responsibility of both the sponsor and the investigator(s) to ensure that this clinical study is conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the ICH guidelines for GCP and applicable regulatory requirements.

Background therapy

Evidence for comparator

Actual start date of recruitment

17 Aug 2017

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Bulgaria: 27

Country: Number of subjects enrolled

Denmark: 34

Country: Number of subjects enrolled

Germany: 11

Country: Number of subjects enrolled

Hungary: 120

Country: Number of subjects enrolled

Lithuania: 16

Country: Number of subjects enrolled

Poland: 444

Country: Number of subjects enrolled

South Africa: 1307

Country: Number of subjects enrolled

Romania: 91

Country: Number of subjects enrolled

Russian Federation: 109

Country: Number of subjects enrolled

Spain: 145

Country: Number of subjects enrolled

Ukraine: 100

Country: Number of subjects enrolled

United Kingdom: 294

Country: Number of subjects enrolled

United States: 609

Worldwide total number of subjects

3307

EEA total number of subjects

888

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)

1876

From 65 to 84 years

1409

85 years and over

Subject disposition

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Recruitment details

Screening details

9157 total participants were screened. 5850 were screen failures: 4681 did not meet criteria, 4 adverse events, 1 Death, 397 investigator/sponsor decision, 130 imaging, 18 lost to follow-up, 93 protocol noncompliance, 225 other, 301 withdrawal of consent. 3307 participants were randomized into the study and 28 were improperly randomized.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Subject, Carer, Data analyst, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo administered orally (PO), twice a day (BID)

Arm type

Placebo

Investigational medicinal product name

Fasinumab-matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

Fasinumab-matching placebo administered subcutaneously

Investigational medicinal product name

Naproxen-matching placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

Naproxen-matching placebo administered orally

Naproxen

Arm description

Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Arm type

Active comparator

Investigational medicinal product name

Naproxen

Investigational medicinal product code

Other name

Pharmaceutical forms

Capsule

Routes of administration

Oral use

Dosage and administration details

500 mg orally, given twice daily (BID)

Fasinumab 1 mg SC Q8W

Arm description

Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Arm type

Experimental

Investigational medicinal product name

fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 mg administered by subcutaneous injection every 8 weeks (Q8W)

Fasinumab 1 mg SC Q4W

Arm description

Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Arm type

Experimental

Investigational medicinal product name

fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

1 mg administered by subcutaneous injection every 4 weeks (Q4W)

Fasinumab 3mg Q4W

Arm description

Fasinumab 3 mg SC Q4W and naproxen-matching placebo, PO, BID

Arm type

Experimental

Investigational medicinal product name

fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

3 mg administered by subcutaneous injection every 4 weeks (Q4W)

Fasinumab 6mg Q8W

Arm description

Fasinumab 6 mg SC Q8W and naproxen-matching placebo, PO, BID

Arm type

Experimental

Investigational medicinal product name

fasinumab

Investigational medicinal product code

REGN475

Other name

Pharmaceutical forms

Solution for injection in pre-filled syringe

Routes of administration

Subcutaneous use

Dosage and administration details

6 mg administered by subcutaneous injection every 8 weeks (Q8W)

Number of subjects in period 1	Placebo	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W	Fasinumab 3mg Q4W	Fasinumab 6mg Q8W
Started	354	1063	551	1054	145	140
Completed	299	919	465	867	102	99
Not completed	55	144	86	187	43	41
Adverse event, serious fatal	3	9	7	9	-	-
Consent withdrawn by subject	24	73	44	97	11	10
Physician decision	-	1	-	2	17	15
BLANK - Need a reason...	-	1	-	-	-	1
Adverse event, non-fatal	5	21	16	35	2	1
Lost to follow-up	3	12	4	7	8	13
Protocol deviation	11	14	6	13	1	-
Lack of efficacy	9	13	9	24	4	1

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo administered orally (PO), twice a day (BID)

Reporting group title

Naproxen

Reporting group description

Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Reporting group title

Fasinumab 1 mg SC Q8W

Reporting group description

Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 1 mg SC Q4W

Reporting group description

Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 3mg Q4W

Reporting group description

Fasinumab 3 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 6mg Q8W

Reporting group description

Fasinumab 6 mg SC Q8W and naproxen-matching placebo, PO, BID

Reporting group values	Placebo	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W	Fasinumab 3mg Q4W	Fasinumab 6mg Q8W	Total
Number of subjects	354	1063	551	1054	145	140	3307
Age Categorical
Units: Participants
Between 18 and 65 years	212	608	300	584	91	81	1876
<=18 years	0	0	0	0	0	0	0
>=65 years	142	455	251	470	54	59	1431
Sex: Female, Male
Units: Participants
Female	265	807	419	793	96	98	2478
Male	89	256	132	261	49	42	829
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	12	26	13	38	6	6	101
Not Hispanic or Latino	339	1032	537	1015	139	134	3196
Unknown or Not Reported	3	5	1	1	0	0	10
Race (NIH/OMB)
Units: Subjects
American Indian or Alaska Native	0	1	1	0	0	0	2
Asian	11	35	29	37	3	1	116
Native Hawaiian or Other Pacific Islander	0	0	0	0	0	0	0
Black or African American	109	315	166	308	47	47	992
White	211	633	307	630	89	86	1956
More than one race	0	0	0	0	0	0	0
Unknown or Not Reported	23	79	48	79	6	6	241

End points

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Reporting group title

Placebo

Reporting group description

Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo administered orally (PO), twice a day (BID)

Reporting group title

Naproxen

Reporting group description

Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Reporting group title

Fasinumab 1 mg SC Q8W

Reporting group description

Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 1 mg SC Q4W

Reporting group description

Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 3mg Q4W

Reporting group description

Fasinumab 3 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 6mg Q8W

Reporting group description

Fasinumab 6 mg SC Q8W and naproxen-matching placebo, PO, BID

Subject analysis set title

SAF Year 1 - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo orally (PO), twice a day (BID)

Subject analysis set title

SAF Year 1 - Naproxen

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Subject analysis set title

SAF Year 1 - 1mg Q8W

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Subject analysis set title

SAF Year 1 - 1mg Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Subject analysis set title

SAF Year 1 and Year 2 - Placebo

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo orally (PO), twice a day (BID)

Subject analysis set title

SAF Year 1 and Year 2 - Naproxen

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Subject analysis set title

SAF Year 1 and Year 2 - 1mg Q8W

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Subject analysis set title

SAF Year 1 and Year 2 - 1mg Q4W

Subject analysis set type

Safety analysis

Subject analysis set description

As treated; Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q4W Compared with that of Participants Treated with Placebo

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End point title

Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q4W Compared with that of Participants Treated with Placebo ^[1]

End point description

The WOMAC index is comprised of 24 parameters grouped in 3 subscales (pain-5 questions, physical function -17 questions and stiffness - 2 questions), with 0-10 grading of each question. The scores for each subscale are summed up, divided by number of questions, and each subscale is reported using Numerical Rating Scale score of 0-10. In addition to subscales, a total score is provided as the sum of normalized subscale scores divided by three, and reported using a Numerical Rating Scale score of 0-10. Higher scores indicate worse pain, stiffness and functional limitations.

End point type

Primary

End point timeframe

Baseline to Week 16

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	155	522
Units: Score on a scale
least squares mean (standard error)	-1.82 ( 0.162 )	-2.49 ( 0.098 )

Placebo vs. fasinumab 1 mg SC Q4W

Comparison groups

Placebo v Fasinumab 1 mg SC Q4W

Number of subjects included in analysis

677

Analysis specification

Pre-specified

Analysis type

P-value

= 0.0002

Method

Mixed models analysis

Parameter type

Least Squares Mean

Point estimate

-0.68

Confidence interval

level

95%

sides

2-sided

lower limit

-1.028

upper limit

-0.324

Variability estimate

Standard error of the mean

Dispersion value

0.18

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q8W Compared with that of Participants Treated with Placebo

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End point title

Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q8W Compared with that of Participants Treated with Placebo ^[2]

End point description

End point type

Primary

End point timeframe

Baseline to Week 16

Notes
[2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	80	254
Units: Score on a scale
least squares mean (standard error)	-2.09 ( 0.231 )	-2.19 ( 0.144 )

Placebo vs. fasinumab 1 mg SC Q8W

Comparison groups

Placebo v Fasinumab 1 mg SC Q8W

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

P-value

= 0.7036

Method

Mixed models analysis

Parameter type

Least Squares Mean

Point estimate

-0.1

Confidence interval

level

95%

sides

2-sided

lower limit

-0.594

upper limit

0.401

Variability estimate

Standard error of the mean

Dispersion value

0.254

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

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End point title

Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo ^[3]

End point description

End point type

Primary

End point timeframe

Baseline to Week 16

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	155	521
Units: Score on a scale
least squares mean (standard error)	-1.71 ( 0.161 )	-2.42 ( 0.096 )

Placebo vs. fasinumab 1 mg SC Q4W

Comparison groups

Placebo v Fasinumab 1 mg SC Q4W

Number of subjects included in analysis

676

Analysis specification

Pre-specified

Analysis type

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

Least Squares Mean

Point estimate

-0.7

Confidence interval

level

95%

sides

2-sided

lower limit

-1.046

upper limit

-0.346

Variability estimate

Standard error of the mean

Dispersion value

0.178

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

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End point title

Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo ^[4]

End point description

End point type

Primary

End point timeframe

Baseline to Week 16

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	80	254
Units: Score on a scale
least squares mean (standard error)	-1.91 ( 0.223 )	-2.09 ( 0.137 )

Placebo vs. fasinumab 1 mg SC Q8W

Comparison groups

Placebo v Fasinumab 1 mg SC Q8W

Number of subjects included in analysis

334

Analysis specification

Pre-specified

Analysis type

P-value

= 0.4605

Method

Mixed models analysis

Parameter type

Least Squares Mean

Point estimate

-0.18

Confidence interval

level

95%

sides

2-sided

lower limit

-0.657

upper limit

0.297

Variability estimate

Standard error of the mean

Dispersion value

0.243

Secondary: Change in the Patient Global Assessment (PGA) Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Placebo

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End point title

Change in the Patient Global Assessment (PGA) Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Placebo ^[5]

End point description

The Patient Global Assessment of OA (PGA) is a patient-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	156	526
Units: Score on a scale
least squares mean (standard error)	-0.64 ( 0.064 )	-0.92 ( 0.040 )

No statistical analyses for this end point

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Naproxen

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End point title

Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Naproxen ^[6]

End point description

PGA is a participant-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	492	526
Units: Score on a scale
least squares mean (standard error)	-0.78 ( 0.040 )	-0.92 ( 0.040 )

No statistical analyses for this end point

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That Of Participants Treated With Placebo

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End point title

Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That Of Participants Treated With Placebo ^[7]

End point description

PGA is a participant-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	123	394
Units: Score on a scale
least squares mean (standard error)	-0.60 ( 0.074 )	-0.79 ( 0.043 )

No statistical analyses for this end point

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q4W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

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End point title

Percentage Of Participants Treated With Fasinumab 1mg Q4W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores ^[8]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	214	639
Units: Percentage of participants
number (not applicable)	43.9	56.2

No statistical analyses for this end point

Secondary: Percentage of Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen, Who Had A Response At Week 16, with Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

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End point title

Percentage of Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen, Who Had A Response At Week 16, with Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores ^[9]

End point description

End point type

Secondary

End point timeframe

Week 16

Notes
[9] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	644	639
Units: Percentage of participants
number (not applicable)	50.5	56.2

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q4W, Compared with That of Participants Treated with Naproxen

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End point title

Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q4W, Compared with That of Participants Treated with Naproxen ^[10]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	345	360
Units: Score on a scale
arithmetic mean (standard deviation)	-2.42 ( 2.095 )	-2.88 ( 2.099 )

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo ^[11]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[11] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	122	391
Units: Score on a scale
least squares mean (standard error)	-1.69 ( 0.188 )	-2.20 ( 0.114 )

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1 mg Q4W, Compared with that of Participants Treated with Naproxen

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End point title

Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1 mg Q4W, Compared with that of Participants Treated with Naproxen ^[12]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	381	391
Units: Score on a scale
least squares mean (standard error)	-2.15 ( 0.115 )	-2.20 ( 0.114 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q4W Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q4W Compared with that of Participants Treated with Placebo ^[13]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 4, 8, 12 and 16

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	192	595
Units: Score on a scale
least squares mean (standard error)	-1.37 ( 0.137 )	-2.25 ( 0.088 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo ^[14]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 36, 40 and 44

Notes
[14] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	133	426
Units: Score on a scale
least squares mean (standard error)	-1.50 ( 0.172 )	-1.99 ( 0.113 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen ^[15]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[15] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	485	521
Units: Score on a scale
least squares mean (standard error)	-1.98 ( 0.101 )	-2.42 ( 0.096 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo ^[16]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	122	390
Units: Score on a scale
least squares mean (standard error)	-1.60 ( 0.186 )	-2.07 ( 0.109 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen ^[17]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[17] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxenand Fasinumab 1 mg SC Q4W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q4W
Number of subjects analysed	378	390
Units: Score on a scale
least squares mean (standard error)	-2.00 ( 0.113 )	-2.07 ( 0.109 )

No statistical analyses for this end point

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

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End point title

Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo ^[18]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 4, 8, 12 and 16

Notes
[18] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	192	596
Units: Score on a scale
least squares mean (standard error)	-1.46 ( 0.140 )	-2.30 ( 0.090 )

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

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End point title

Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo ^[19]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 36, 40 and 44

Notes
[19] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q4W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	133	427
Units: Score on a scale
least squares mean (standard error)	-1.57 ( 0.184 )	-2.06 ( 0.118 )

No statistical analyses for this end point

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with That of Participants Treated with Placebo

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End point title

Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with That of Participants Treated with Placebo ^[20]

End point description

PGA is a participant-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[20] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	80	257
Units: Score on a scale
least squares mean (standard error)	-0.79 ( 0.094 )	-0.77 ( 0.057 )

No statistical analyses for this end point

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1 mg Q8W Compared with That of Participants Treated with Naproxen

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End point title

Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1 mg Q8W Compared with That of Participants Treated with Naproxen ^[21]

End point description

PGA is a participant-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[21] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q8W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q8W
Number of subjects analysed	245	257
Units: Score on a scale
least squares mean (standard error)	-0.82 ( 0.057 )	-0.77 ( 0.057 )

No statistical analyses for this end point

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That Of Participants Treated With Placebo

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End point title

Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That Of Participants Treated With Placebo ^[22]

End point description

PGA is a participant-rated assessment of current disease state on a 5-point Likert scale (1 = very good; 2 = good; 3 = fair; 4 = poor; and 5 = very poor).

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[22] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q4W
Number of subjects analysed	62	193
Units: Score on a scale
least squares mean (standard error)	-0.74 ( 0.1115 )	-0.75 ( 0.064 )

No statistical analyses for this end point

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q8W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

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End point title

Percentage Of Participants Treated With Fasinumab 1mg Q8W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores ^[23]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[23] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	102	304
Units: Percentage of participants
number (not applicable)	53.9	52.3

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q8W, Compared with That of Participants Treated with Naproxen

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End point title

Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q8W, Compared with That of Participants Treated with Naproxen ^[24]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[24] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q8W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q8W
Number of subjects analysed	170	171
Units: Score on a scale
least squares mean (standard error)	-2.41 ( 0.155 )	-2.53 ( 0.154 )

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo ^[25]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[25] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	62	189
Units: Score on a scale
least squares mean (standard error)	-1.77 ( 0.276 )	-1.99 ( 0.163 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q8W Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q8W Compared with that of Participants Treated with Placebo ^[26]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 4, 8, 12 and 16

Notes
[26] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	94	291
Units: Score on a scale
least squares mean (standard error)	-1.61 ( 0.196 )	-2.04 ( 0.127 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo ^[27]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 36, 40 and 44

Notes
[27] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	69	210
Units: Score on a scale
least squares mean (standard error)	-1.62 ( 0.261 )	-1.69 ( 0.166 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Naproxen

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Naproxen ^[28]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 16

Notes
[28] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Naproxen and Fasinumab 1 mg SC Q8W arms only.

End point values	Naproxen	Fasinumab 1 mg SC Q8W
Number of subjects analysed	241	254
Units: Score on a scale
least squares mean (standard error)	-2.04 ( 0.140 )	-2.09 ( 0.137 )

No statistical analyses for this end point

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

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End point title

Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo ^[29]

End point description

End point type

Secondary

End point timeframe

Baseline to Week 44

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	62	189
Units: Score on a scale
least squares mean (standard error)	-1.76 ( 0.262 )	-1.90 ( 0.157 )

No statistical analyses for this end point

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

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End point title

Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo ^[30]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 4, 8, 12 and 16

Notes
[30] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	94	291
Units: Score on a scale
least squares mean (standard error)	-1.73 ( 0.202 )	-2.11 ( 0.131 )

No statistical analyses for this end point

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

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End point title

Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo ^[31]

End point description

End point type

Secondary

End point timeframe

Baseline to average score across weeks 36, 40 and 44

Notes
[31] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint applies to Placebo and Fasinumab 1 mg SC Q8W arms only.

End point values	Placebo	Fasinumab 1 mg SC Q8W
Number of subjects analysed	69	210
Units: Score on a scale
least squares mean (standard error)	-1.69 ( 0.271 )	-1.80 ( 0.169 )

No statistical analyses for this end point

Secondary: Number of Participants with Adjudicated Arthropathy (AA) (as confirmed by adjudication) - Year 1

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End point title

Number of Participants with Adjudicated Arthropathy (AA) (as confirmed by adjudication) - Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Participants	4	27	40	102

No statistical analyses for this end point

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 2

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End point title

Number of Participants with AA (as confirmed by adjudication) - Year 2 ^[32]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[32] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Placebo	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	137	402	193	371
Units: Participants	2	7	11	53

No statistical analyses for this end point

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 1 and Year 2

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End point title

Number of Participants with AA (as confirmed by adjudication) - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E (Extension)

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Participants	6	33	50	152

No statistical analyses for this end point

Secondary: Number of Participants with Destructive Arthropathy (DA) (as confirmed by adjudication) - Year 1

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End point title

Number of Participants with Destructive Arthropathy (DA) (as confirmed by adjudication) - Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Participants	0	1	2	7

No statistical analyses for this end point

Secondary: Number of Participants with DA (as confirmed by adjudication) - Year 2

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End point title

Number of Participants with DA (as confirmed by adjudication) - Year 2 ^[33]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[33] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Placebo	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	137	402	193	371
Units: Participants	0	0	0	4

No statistical analyses for this end point

Secondary: Number of Participants with DA (as confirmed by adjudication) - Year 1 and Year 2

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End point title

Number of Participants with DA (as confirmed by adjudication) - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Participants	0	1	2	11

No statistical analyses for this end point

Secondary: Number of Treatment Emergent Adverse Events (TEAEs) - Year 1

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End point title

Number of Treatment Emergent Adverse Events (TEAEs) - Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Events	1063	3641	1985	3901

No statistical analyses for this end point

Secondary: Number of TEAEs - Year 2

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End point title

Number of TEAEs - Year 2 ^[34]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[34] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	554	190	385
Units: Events	973	277	808

No statistical analyses for this end point

Secondary: Number of TEAEs - Year 1 and Year 2

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End point title

Number of TEAEs - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Events	1317	4348	2271	4712

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 1

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End point title

Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Participants	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 2

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End point title

Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 2 ^[35]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[35] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	554	190	385
Units: Participants	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 1 and Year 2

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End point title

Number of Participants with at Least 1 Sympathetic Nervous System (SNS) Dysfunction Adverse Event of Special Interest (AESI) - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Participants	1	0	0	0

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 1

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End point title

Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Participants	18	43	29	70

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 2

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End point title

Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 2 ^[36]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[36] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	554	190	385
Units: Participants	16	6	12

No statistical analyses for this end point

Secondary: Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 1 and Year 2

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End point title

Number of Participants with at Least 1 Peripheral Sensory Neuropathy AESI That Require a Neurology or Other Specialty Consultation - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Participants	23	51	35	82

No statistical analyses for this end point

Secondary: Number of Participants with Any Type of All-Cause Joint Replacement (JR) in Year 1

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End point title

Number of Participants with Any Type of All-Cause Joint Replacement (JR) in Year 1

End point description

End point type

Secondary

End point timeframe

Baseline to Week 52

End point values	SAF Year 1 - Placebo	SAF Year 1 - Naproxen	SAF Year 1 - 1mg Q8W	SAF Year 1 - 1mg Q4W
Number of subjects analysed	352	1056	554	1052
Units: Participants	12	33	31	67

No statistical analyses for this end point

Secondary: Number of Participants with Any Type of All-Cause JR in Year 2

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End point title

Number of Participants with Any Type of All-Cause JR in Year 2 ^[37]

End point description

End point type

Secondary

End point timeframe

First dose of study drug in Year 2 through week 104E

Notes
[37] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: Endpoint did not apply to the 3mg and 6mg dosing arms as those were discontinued.

End point values	Naproxen	Fasinumab 1 mg SC Q8W	Fasinumab 1 mg SC Q4W
Number of subjects analysed	554	190	385
Units: Participants	22	12	33

No statistical analyses for this end point

Secondary: Number of Participants with Any Type of All-Cause JR - Year 1 and Year 2

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End point title

Number of Participants with Any Type of All-Cause JR - Year 1 and Year 2

End point description

End point type

Secondary

End point timeframe

Day 1 through week 104E

End point values	SAF Year 1 and Year 2 - Placebo	SAF Year 1 and Year 2 - Naproxen	SAF Year 1 and Year 2 - 1mg Q8W	SAF Year 1 and Year 2 - 1mg Q4W
Number of subjects analysed	353	1056	553	1052
Units: Participants	19	47	44	100

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From first dose up to week 124

Adverse event reporting additional description

As treated population

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

23.1

Reporting group title

Placebo

Reporting group description

Fasinumab-matching placebo administered by subcutaneous (SC) injection, every 4 weeks (Q4W) and naproxen-matching placebo administered orally (PO), twice a day (BID)

Reporting group title

Naproxen

Reporting group description

Fasinumab-matching placebo SC Q4W and naproxen 500 mg PO, BID

Reporting group title

Fasinumab 1mg Q8W

Reporting group description

Fasinumab 1 mg SC Q8W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 1mg Q4W

Reporting group description

Fasinumab 1 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 3mg Q4W

Reporting group description

Fasinumab 3 mg SC Q4W and naproxen-matching placebo, PO, BID

Reporting group title

Fasinumab 6mg Q8W

Reporting group description

Fasinumab 6 mg SC Q8W and naproxen-matching placebo, PO, BID

Serious adverse events	Placebo	Naproxen	Fasinumab 1mg Q8W	Fasinumab 1mg Q4W	Fasinumab 3mg Q4W	Fasinumab 6mg Q8W
Total subjects affected by serious adverse events
subjects affected / exposed	49 / 352 (13.92%)	103 / 1056 (9.75%)	81 / 554 (14.62%)	175 / 1052 (16.63%)	7 / 145 (4.83%)	6 / 139 (4.32%)
number of deaths (all causes)	5	13	12	13	0	0
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Bladder cancer
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder neoplasm
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	2 / 554 (0.36%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chronic myeloid leukaemia
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic cancer metastatic
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteosarcoma
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Prostate cancer metastatic
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign ovarian tumour
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Benign soft tissue neoplasm
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Breast cancer recurrent
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatic neoplasm
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intraductal proliferative breast lesion
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meningioma
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Metastases to bone
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Neoplasm malignant
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer metastatic
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oesophageal carcinoma
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma metastatic
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatic neoplasm
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal hamartoma
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Retroperitoneal neoplasm
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular disorders
Aortic stenosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Aortic dissection
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	1 / 145 (0.69%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hypertensive urgency
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Knee arthroplasty
subjects affected / exposed	7 / 352 (1.99%)	7 / 1056 (0.66%)	4 / 554 (0.72%)	17 / 1052 (1.62%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 7	1 / 7	0 / 4	4 / 20	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip arthroplasty
subjects affected / exposed	0 / 352 (0.00%)	5 / 1056 (0.47%)	5 / 554 (0.90%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 5	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint arthroplasty
subjects affected / exposed	2 / 352 (0.57%)	3 / 1056 (0.28%)	4 / 554 (0.72%)	8 / 1052 (0.76%)	0 / 145 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 2	1 / 3	0 / 4	0 / 8	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint resurfacing surgery
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Knee operation
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Sudden death
subjects affected / exposed	1 / 352 (0.28%)	3 / 1056 (0.28%)	1 / 554 (0.18%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 3	0 / 1	0 / 3	0 / 0	0 / 0
Death
subjects affected / exposed	2 / 352 (0.57%)	2 / 1056 (0.19%)	1 / 554 (0.18%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 2	0 / 2	0 / 1	0 / 2	0 / 0	0 / 0
Adverse drug reaction
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedema peripheral
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical polyp
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Endometrial hyperplasia
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ovarian cyst
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Apnoea
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Asthma
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pulmonary embolism
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	2 / 554 (0.36%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Psychotic disorder
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Substance abuse
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pseudodementia
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Device loosening
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Gun shot wound
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb injury
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Soft tissue injury
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Thoracic vertebral fracture
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Deep vein thrombosis postoperative
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Fractured sacrum
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint injury
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Postoperative wound complication
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon injury
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Upper limb fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Hydrocele
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute coronary syndrome
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	2 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	1 / 352 (0.28%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial infarction
subjects affected / exposed	1 / 352 (0.28%)	2 / 1056 (0.19%)	2 / 554 (0.36%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Atrial fibrillation
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiovascular disorder
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute myocardial infarction
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	4 / 1052 (0.38%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 4	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Atrial tachycardia
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac arrest
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Cardiac failure
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac failure congestive
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	2 / 554 (0.36%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Nervous system disorders
Carotid artery aneurysm
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	2 / 554 (0.36%)	5 / 1052 (0.48%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	1 / 2	0 / 5	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 2	0 / 0	0 / 0
Guillain-Barre syndrome
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vascular encephalopathy
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	2 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cerebrospinal fistula
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hemiplegic migraine
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar radiculopathy
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Muscle tone disorder
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Myelopathy
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Radiculopathy
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Syncope
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	2 / 352 (0.57%)	4 / 1056 (0.38%)	2 / 554 (0.36%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 4	2 / 4	1 / 2	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eye disorders
Cataract
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Eyelid ptosis
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Hiatus hernia
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal hernia
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Oedematous pancreatitis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peptic ulcer
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Anal fissure
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Food poisoning
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Gastrointestinal inflammation
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal haemorrhage
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intestinal perforation
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Volvulus of small bowel
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Hepatitis alcoholic
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholangitis acute
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	1 / 352 (0.28%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Acute kidney injury
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bladder prolapse
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Prerenal failure
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
Renal impairment
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	4 / 352 (1.14%)	11 / 1056 (1.04%)	10 / 554 (1.81%)	8 / 1052 (0.76%)	1 / 145 (0.69%)	2 / 139 (1.44%)
occurrences causally related to treatment / all	1 / 4	2 / 11	0 / 11	1 / 9	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rapidly progressive osteoarthritis
subjects affected / exposed	1 / 352 (0.28%)	4 / 1056 (0.38%)	13 / 554 (2.35%)	44 / 1052 (4.18%)	1 / 145 (0.69%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	1 / 1	5 / 7	7 / 13	39 / 53	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteoarthritis
subjects affected / exposed	3 / 352 (0.85%)	3 / 1056 (0.28%)	3 / 554 (0.54%)	6 / 1052 (0.57%)	1 / 145 (0.69%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 3	0 / 3	0 / 3	0 / 6	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	2 / 554 (0.36%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Haemarthrosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal stenosis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	1 / 145 (0.69%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Exostosis
subjects affected / exposed	1 / 352 (0.28%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Joint effusion
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Limb mass
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	1 / 139 (0.72%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 2	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Spinal synovial cyst
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Subchondral insufficiency fracture
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	1 / 554 (0.18%)	1 / 1052 (0.10%)	1 / 145 (0.69%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1	0 / 1	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Vertebral foraminal stenosis
subjects affected / exposed	0 / 352 (0.00%)	0 / 1056 (0.00%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
COVID-19 pneumonia
subjects affected / exposed	2 / 352 (0.57%)	3 / 1056 (0.28%)	1 / 554 (0.18%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 3	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
COVID-19
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	2 / 554 (0.36%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 2	0 / 1	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 352 (0.28%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	1 / 1052 (0.10%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	2 / 554 (0.36%)	1 / 1052 (0.10%)	1 / 145 (0.69%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	0 / 352 (0.00%)	2 / 1056 (0.19%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Arthritis infective
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Diverticulitis
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Empyema
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastric ulcer helicobacter
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infectious pleural effusion
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Peritonsillar abscess
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	1 / 554 (0.18%)	3 / 1052 (0.29%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1	0 / 3	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 1	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Post procedural infection
subjects affected / exposed	0 / 352 (0.00%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	0 / 1052 (0.00%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 352 (0.28%)	1 / 1056 (0.09%)	0 / 554 (0.00%)	2 / 1052 (0.19%)	0 / 145 (0.00%)	0 / 139 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0	0 / 2	0 / 0

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Clinical trials

Clinical Trial Results: A Phase 3 Randomized, Double-blind, Multi-dose, Placebo and Naproxen-Controlled Study to Evaluate the Efficacy and Safety of Fasinumab in Patients with Pain Due to Osteoarthritis of the Knee or Hip

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q4W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q4W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q8W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Pain Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg SC Q8W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

Primary: Change in the WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

Secondary: Change in the Patient Global Assessment (PGA) Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Placebo

Secondary: Change in the Patient Global Assessment (PGA) Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Placebo

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Naproxen

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W Compared with That of Participants Treated with Naproxen

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That Of Participants Treated With Placebo

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That Of Participants Treated With Placebo

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q4W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q4W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Percentage of Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen, Who Had A Response At Week 16, with Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Percentage of Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen, Who Had A Response At Week 16, with Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q4W, Compared with That of Participants Treated with Naproxen

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q4W, Compared with That of Participants Treated with Naproxen

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1 mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1 mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q4W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q4W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q4W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q4W, Compared with that of Participants Treated with Naproxen

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q4W Compared With That of Participants Treated With Placebo

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with That of Participants Treated with Placebo

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W Compared with That of Participants Treated with Placebo

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1 mg Q8W Compared with That of Participants Treated with Naproxen

Secondary: Change in the PGA Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1 mg Q8W Compared with That of Participants Treated with Naproxen

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That Of Participants Treated With Placebo

Secondary: Change In The PGA Scores From Baseline To Week 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That Of Participants Treated With Placebo

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q8W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Percentage Of Participants Treated With Fasinumab 1mg Q8W, Compared With That of Participants Treated With Placebo, Who Had A Response At Week 16, With Response Defined As An Improvement By ≥30% In The WOMAC Pain Subscale Scores

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q8W, Compared with That of Participants Treated with Naproxen

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 16 In Participants Treated with Fasinumab 1mg Q8W, Compared with That of Participants Treated with Naproxen

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Pain Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q8W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 4, 8, 12 and 16, in Participants Treated with Fasinumab 1 mg Q8W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to the Average Score Across Weeks 36, 40 and 44 in Participants Treated with Fasinumab 1mg Q8W Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 16 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Naproxen

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

Secondary: Change in WOMAC Physical Function Subscale Scores from Baseline to Week 44 in Participants Treated with Fasinumab 1mg Q8W, Compared with that of Participants Treated with Placebo

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

Secondary: Change In WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 4, 8, 12 And 16, in Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

Secondary: Change in WOMAC Pain Subscale Scores From Baseline To The Average Score Across Weeks 36, 40 And 44 In Participants Treated With Fasinumab 1mg Q8W Compared With That of Participants Treated With Placebo

Secondary: Number of Participants with Adjudicated Arthropathy (AA) (as confirmed by adjudication) - Year 1

Secondary: Number of Participants with Adjudicated Arthropathy (AA) (as confirmed by adjudication) - Year 1

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 2

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 2

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 1 and Year 2

Secondary: Number of Participants with AA (as confirmed by adjudication) - Year 1 and Year 2

Secondary: Number of Participants with Destructive Arthropathy (DA) (as confirmed by adjudication) - Year 1

Secondary: Number of Participants with Destructive Arthropathy (DA) (as confirmed by adjudication) - Year 1

Clinical Trial Results:
A Phase 3 Randomized, Double-blind, Multi-dose, Placebo and Naproxen-Controlled Study to Evaluate the Efficacy and Safety of Fasinumab in Patients with Pain Due to Osteoarthritis of the Knee or Hip