Trial Outcomes & Findings for Open Label Long-Term Safety Study of Certolizumab Pegol (CZP) for Patients With Rheumatoid Arthritis (NCT NCT00160693)

Last Updated: 2018-08-01

Results Overview

An AE is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. First dose of CZP was at Baseline of one of the feeder studies C87011 \[NCT00548834\] or C87014 \[NCT00544154\] for subjects randomized to CZP, or at First Visit (Week 0) of this study for subjects randomized to Placebo.

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

402 participants

Primary outcome timeframe

From first dose of CZP up to 8 years

Results posted on

2018-08-01

Participant Flow

Subjects must have participated in CZP trial C87011 \[NCT00548834\] or C87014 \[NCT00544154\] for at least 12 weeks to be eligible to enter the study. All enrolled subjects who received at least one dose of study medication are included in the Safety Set (SS).

Participant Flow and Baseline Characteristics refer to the Safety Set (SS). Baseline Characteristics were measured at Baseline of the respective feeder study.

Participant milestones

Participant milestones
Measure	Certolizumab Pegol 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Overall Study STARTED	402
Overall Study COMPLETED	167
Overall Study NOT COMPLETED	235

Reasons for withdrawal

Reasons for withdrawal
Measure	Certolizumab Pegol 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Overall Study Adverse Event	97
Overall Study Lack of Efficacy	30
Overall Study Protocol Violation	24
Overall Study Lost to Follow-up	15
Overall Study Withdrawal by Subject	54
Overall Study Study terminated by sponsor	15

Baseline Characteristics

Open Label Long-Term Safety Study of Certolizumab Pegol (CZP) for Patients With Rheumatoid Arthritis

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Age, Categorical <=18 years	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	327 Participants n=5 Participants
Age, Categorical >=65 years	75 Participants n=5 Participants
Age, Continuous	53.4 years STANDARD_DEVIATION 12.1 • n=5 Participants
Sex: Female, Male Female	303 Participants n=5 Participants
Sex: Female, Male Male	99 Participants n=5 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants n=5 Participants
Race (NIH/OMB) Asian	3 Participants n=5 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants
Race (NIH/OMB) Black or African American	19 Participants n=5 Participants
Race (NIH/OMB) White	363 Participants n=5 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants
Race (NIH/OMB) Unknown or Not Reported	17 Participants n=5 Participants
Region of Enrollment United States	160 participants n=5 Participants
Region of Enrollment Czech Republic	81 participants n=5 Participants
Region of Enrollment Belgium	11 participants n=5 Participants
Region of Enrollment Ireland	8 participants n=5 Participants
Region of Enrollment Austria	19 participants n=5 Participants
Region of Enrollment Germany	87 participants n=5 Participants
Region of Enrollment United Kingdom	36 participants n=5 Participants
Weight	78.00 kilogram (kg) STANDARD_DEVIATION 17.88 • n=5 Participants
Height	166.4 centimeter (cm) STANDARD_DEVIATION 8.6 • n=5 Participants
Body Mass Index (BMI)	28.20 kilogram/ meter^2 (kg / m^2) STANDARD_DEVIATION 6.34 • n=5 Participants
Disease Duration	9.46 years STANDARD_DEVIATION 8.13 • n=5 Participants

PRIMARY outcome

Timeframe: From first dose of CZP up to 8 years

Population: Safety Set (SS).

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects With at Least One Adverse Event (AE) During the Study Period of 8 Years	93.5 percentage of subjects

PRIMARY outcome

Timeframe: From First Visit (Week 0 in this study) up to 8 years

Population: Safety Set (SS).

An AE is any untoward medical occurrence in a subject or trial subject that is administered a drug or biologic (medicinal product) or that is using a medical device. The event does not necessarily have a causal relationship with that treatment or usage. The results of this Primary Outcome Measure are summarized from the Adverse Event pages of the Case Report Forms.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Who Withdrew Due to an Adverse Event (AE) During the Study Period of 8 Years	24.9 percentage of subjects

SECONDARY outcome

Timeframe: From Baseline to Week 52

Population: Of the 402 subjects in the Safety Set (SS), 370 subjects are included in this analysis, because they had available data at Baseline and Week 52.

The assessments are based on a 20% or greater improvement from Baseline to Week 52 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=370 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 52	58.1 percentage of subjects Interval 53.1 to 63.1

SECONDARY outcome

Timeframe: From Baseline to Week 100

Population: Of the 402 subjects in the Safety Set (SS), 275 subjects are included in this analysis, because they had available data at Baseline and Week 100.

The assessments are based on a 20% or greater improvement from Baseline to Week 100 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=275 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 100	60.0 percentage of subjects Interval 54.2 to 65.8

SECONDARY outcome

Timeframe: From Baseline to Week 160

Population: Of the 402 subjects in the Safety Set (SS), 247 subjects are included in this analysis, because they had available data at Baseline and Week 160.

The assessments are based on a 20% or greater improvement from Baseline to Week 160 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=247 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 160	68.4 percentage of subjects Interval 62.6 to 74.2

SECONDARY outcome

Timeframe: From Baseline to Week 208

Population: Of the 402 subjects in the Safety Set (SS), 223 subjects are included in this analysis, because they had available data at Baseline and Week 208.

The assessments are based on a 20% or greater improvement from Baseline to Week 208 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=223 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 208	72.6 percentage of subjects Interval 66.8 to 78.5

SECONDARY outcome

Timeframe: From Baseline to Week 256

Population: Of the 402 subjects in the Safety Set (SS), 211 subjects are included in this analysis, because they had available data at Baseline and Week 256.

The assessments are based on a 20% or greater improvement from Baseline to Week 256 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=211 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 256	75.4 percentage of subjects Interval 69.5 to 81.2

SECONDARY outcome

Timeframe: From Baseline to Week 316

Population: Of the 402 subjects in the Safety Set (SS), 140 subjects are included in this analysis, because they had available data at Baseline and Week 316.

The assessments are based on a 20% or greater improvement from Baseline to Week 316 in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP). Baseline is Baseline of the respective feeder study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=140 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Week 316	76.4 percentage of subjects Interval 69.4 to 83.5

SECONDARY outcome

Timeframe: From Baseline to Completion Visit/ early Withdrawal Visit, up to 8 years

Population: Safety Set (SS).

The assessments are based on a 20% or greater improvement from Baseline to the Completion Visit or early Withdrawal Visit in the number of tender joints, a 20% or more improvement in the number of swollen joints, and a 20% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 20% Response Criteria (ACR20) at Completion Visit or Early Withdrawal Visit	57.2 percentage of subjects Interval 52.4 to 62.1

SECONDARY outcome

Timeframe: From Baseline to Completion Visit/ early Withdrawal Visit, up to 8 years

Population: Safety Set (SS).

The assessments are based on a 50% or greater improvement from Baseline to the Completion Visit or early Withdrawal Visit in the number of tender joints, a 50% or more improvement in the number of swollen joints, and a 50% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 50% Response Criteria (ACR50) at Completion Visit or Early Withdrawal Visit	27.6 percentage of subjects Interval 23.2 to 32.0

SECONDARY outcome

Timeframe: From Baseline to Completion Visit/ early Withdrawal Visit, up to 8 years

Population: Safety Set (SS).

The assessments are based on a 70% or greater improvement from Baseline to the Completion Visit or early Withdrawal Visit in the number of tender joints, a 70% or more improvement in the number of swollen joints, and a 70% or greater improvement in 3 of the 5 remaining core set measures: Patient's Global Assessment of Disease Activity (PtGADA), Physician's Global Assessment of Disease Activity (PhGADA), Patient's Assessment of Arthritis Pain (PtAAP), physical function as assessed by the Health Assessment Questionnaire - Disability Index (HAQ-DI) and C-Reactive Protein (CRP).

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Meeting the American College of Rheumatology 70% Response Criteria (ACR70) at Completion Visit or Early Withdrawal Visit	7.7 percentage of subjects Interval 5.1 to 10.3

SECONDARY outcome

Timeframe: From Baseline to Completion Visit/ early Withdrawal Visit, up to 8 years

Population: Of the 402 subjects in the Safety Set (SS), 400 subjects are included in this analysis, because they had available data at Baseline and Completion or early Withdrawal Visit.

The HAQ-DI assesses the degree of difficulty experienced in eight domains (Dressing and Grooming, Arising, Eating, Walking, Hygiene, Reach, Gripping, Other Activities) of daily living activities using 20 questions. The HAQ-DI is calculated by summing the domain scores and dividing them by the number of domains. It ranges from 0 (no difficulty) to 3 (unable to do). Negative values indicate an improvement from Baseline to the Post-Baseline Visit with larger negative values showing a better improvement.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=400 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Change From Baseline in Health Assessment Questionnaire-Disability Index (HAQ- DI) at Completion Visit or Early Withdrawal Visit	-0.305 units on a scale Standard Deviation 0.620

SECONDARY outcome

Timeframe: From First Visit (Week 0 in this study) up to 8 years

Population: Safety Set (SS).

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Who Withdrew Due to Lack of Efficacy During the Study Period of 8 Years	7.5 percentage of subjects

SECONDARY outcome

Timeframe: From First Visit (Week 0 in this study) up to 8 years

Population: Safety Set (SS).

This Secondary Outcome Measure shows additional arthritis medications received by at least 20% of subjects during the 8-year study.

Outcome measures

Outcome measures
Measure	Certolizumab Pegol n=402 Participants 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Acetylsalicylic acid	21.9 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Celecoxib	22.9 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Diclofenac	23.4 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Folic acid	65.2 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Ibuprofen	26.4 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Methotrexate	60.9 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Methylprednisolone	33.8 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Other Immunosuppressive agents	25.9 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Paracetamol	29.6 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Prednisolone	20.4 percentage of subjects
Percentage of Subjects Utilizing Common Additional Arthritis Medications During the Study Period of 8 Years Prednisone	39.3 percentage of subjects

Adverse Events

Certolizumab Pegol

Serious events: 184 serious events

Other events: 348 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	Certolizumab Pegol n=402 participants at risk 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Gastrointestinal disorders Abdominal adhesions	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Abdominal hernia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Abscess intestinal	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Abscess neck	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Acute coronary syndrome	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Acute myocardial infarction	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Acute prerenal failure	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Acute respiratory failure	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Anaemia	0.50% 2/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Angina pectoris	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Angina unstable	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Aortic aneurysm	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Arrhythmia	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Arterial occlusive disease	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Arterial stenosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Arthralgia	0.50% 2/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Arthritis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Arthritis infective	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Arthrofibrosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Asthenia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Atrial fibrillation	1.00% 4/402 • Number of events 5 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Atrioventricular block	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Back pain	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Basal cell carcinoma	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Benign prostatic hyperplasia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Bile duct stone	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Bradycardia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Brain contusion	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Breast cancer	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Bronchitis	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Bronchitis acute	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Bronchopneumonia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Bursitis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Cardiac arrest	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Cardiac failure	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Cellulitis	1.00% 4/402 • Number of events 9 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Cerebral ischaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Cerebrovascular accident	0.75% 3/402 • Number of events 6 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Chest pain	0.75% 3/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Chills	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Cholangitis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Cholangitis suppurative	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Cholecystitis	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Cholecystitis acute	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Cholecystitis chronic	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Cholecystitis infective	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Cholelithiasis	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Cholesteatoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Chronic obstructive pulmonary disease	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Chronic sinusitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Chronic tonsillitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Circulatory collapse	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Clostridial infection	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Colon adenoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Eye disorders Conjunctivitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Contrast media reaction	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Contusion	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Coronary artery disease	1.5% 6/402 • Number of events 6 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Coronary artery stenosis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Cough	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Cystocele	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Deep vein thrombosis	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Dehydration	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Psychiatric disorders Depression	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Device failure	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Device related infection	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Diabetes mellitus	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Diabetic ketoacidosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Diarrhoea	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Diffuse large B-cell lymphoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Disturbance in attention	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Diverticular perforation	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Diverticulitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Diverticulum	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Diverticulum duodenal	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Dizziness postural	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Immune system disorders Drug hypersensitivity	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Embolism	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Empyema	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Endometriosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Epilepsy	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Erysipelas	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Skin and subcutaneous tissue disorders Erythema	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Escherichia sepsis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Exostosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Fall	0.75% 3/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Femoral neck fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Femur fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Finger deformity	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Fistula	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Forearm fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Foreign body trauma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Gastric ulcer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Gastritis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Gastritis erosive	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Gastroenteritis	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Gastroenteritis clostridial	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Gastroenteritis viral	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Gastrointestinal haemorrhage	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Global amnesia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Endocrine disorders Goitre	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Grand mal convulsion	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Groin pain	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Headache	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Hepatitis cholestatic	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Hepatotoxicity	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Herpes simplex	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Herpes zoster	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Hiatus hernia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Hilar lymphadenopathy	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Hip fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Histoplasmosis disseminated	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Humerus fracture	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Hypertension	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Hypertensive crisis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Endocrine disorders Hyperthyroidism	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Hypokalaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Hyponatraemia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Hypotension	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Hypovolaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Ileus paralytic	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Impaired healing	0.50% 2/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Incisional hernia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Incontinence	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Infected skin ulcer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Infection	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Inflammatory bowel disease	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Inguinal hernia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Injury	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Intervertebral disc degeneration	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Intervertebral disc disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Intervertebral disc protrusion	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Iron deficiency anaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Ischaemic stroke	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Joint destruction	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Joint dislocation	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Joint swelling	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Leukoplakia oral	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Liver abscess	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Liver disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Lobar pneumonia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Loss of consciousness	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Lower respiratory tract infection	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Lumbar spinal stenosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Lumbar vertebral fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma stage I	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung cancer metastatic	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung neoplasm malignant	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Lymph node tuberculosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Lymphadenitis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lymphocytic leukaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Eye disorders Maculopathy	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Malaise	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Malignant melanoma in situ	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Mastitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Medical device complication	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Medication error	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Melaena	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Menorrhagia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Metrorrhagia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Mixed incontinence	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Multi-organ failure	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Myalgia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Myocardial infarction	1.2% 5/402 • Number of events 5 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Myocardial ischaemia	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Necrotising fasciitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Nephrolithiasis	1.00% 4/402 • Number of events 5 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Neuropathy peripheral	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Neutropenic sepsis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Non-cardiac chest pain	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Metabolism and nutrition disorders Obesity	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Oedema	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Oedema peripheral	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Oedematous pancreatitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Oesophageal rupture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Oncocytoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Eye disorders Optic nerve disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Osteoarthritis	4.0% 16/402 • Number of events 21 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Ovarian cancer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Pain in extremity	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Pancreatitis acute	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Psychiatric disorders Panic disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Paraesthesia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Parathyroid tumour benign	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Patella fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pelvic abscess	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Pelvic fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Hepatobiliary disorders Perforation bile duct	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Peripheral ischaemia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Peritonitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Pleurisy	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pneumocystis jiroveci pneumonia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pneumonia	2.2% 9/402 • Number of events 10 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pneumonia legionella	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pneumonia staphylococcal	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pneumonia streptococcal	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Psychiatric disorders Post-traumatic stress disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostate cancer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Prostatic adenoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Pubic rami fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Pulmonary embolism	1.00% 4/402 • Number of events 4 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pulmonary tuberculosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Purulent synovitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pyelonephritis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pyelonephritis acute	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Pyrexia	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Radius fracture	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Rectal haemorrhage	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Rectocele	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Renal cell carcinoma stage I	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Renal colic	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Renal failure acute	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Respiratory failure	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Respiratory tract infection viral	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	4.0% 16/402 • Number of events 20 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Rheumatoid nodule	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Rotator cuff syndrome	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Sepsis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Sinus bradycardia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Cardiac disorders Sinus tachycardia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Skin and subcutaneous tissue disorders Skin ulcer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Spinal column stenosis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Spinal compression fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Spinal osteoarthritis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Squamous cell carcinoma of skin	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Staphylococcal infection	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Sternal fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Stomatitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Stress incontinence	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Subarachnoid haemorrhage	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Subcutaneous abscess	0.50% 2/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Subdural haematoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Subileus	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Syncope	0.50% 2/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Surgical and medical procedures Synovectomy	0.25% 1/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Synovial cyst	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Synovial rupture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Synovitis	0.50% 2/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Tendon disorder	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Tendon injury	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Tendon rupture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Tenosynovitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Thrombocytopenia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Thrombophlebitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid gland cancer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Thyroid neoplasm	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Tibia fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Toe deformity	1.2% 5/402 • Number of events 5 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tonsil cancer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Tonsillitis	0.50% 2/402 • Number of events 2 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Tracheobronchitis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Transient ischaemic attack	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Tuberculosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Ulna fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Umbilical hernia	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Upper limb fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Renal and urinary disorders Urinary incontinence	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Urinary tract infection	0.75% 3/402 • Number of events 3 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine cancer	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Uterine leiomyoma	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Reproductive system and breast disorders Vaginal prolapse	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Varicose vein	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Venous thrombosis	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Wrist fracture	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications XIth nerve injury	0.25% 1/402 • Number of events 1 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.

Other adverse events

Other adverse events
Measure	Certolizumab Pegol n=402 participants at risk 400 mg of Certolizumab Pegol subcutaneously every 4 Weeks.
Gastrointestinal disorders Abdominal pain upper	5.5% 22/402 • Number of events 31 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Investigations Alanine aminotransferase increased	6.7% 27/402 • Number of events 34 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Blood and lymphatic system disorders Anaemia	6.2% 25/402 • Number of events 31 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Arthralgia	16.2% 65/402 • Number of events 118 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Back pain	22.4% 90/402 • Number of events 137 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Bronchitis	14.4% 58/402 • Number of events 89 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Bronchitis acute	6.2% 25/402 • Number of events 45 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Bursitis	7.0% 28/402 • Number of events 40 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Eye disorders Conjunctivitis	7.2% 29/402 • Number of events 34 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Constipation	6.0% 24/402 • Number of events 29 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Contusion	7.5% 30/402 • Number of events 44 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Cough	20.4% 82/402 • Number of events 126 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Cystitis	8.2% 33/402 • Number of events 45 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Psychiatric disorders Depression	9.7% 39/402 • Number of events 49 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Diarrhoea	15.9% 64/402 • Number of events 135 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Dizziness	10.4% 42/402 • Number of events 59 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Dyspepsia	10.2% 41/402 • Number of events 60 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Dyspnoea	5.5% 22/402 • Number of events 32 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Injury, poisoning and procedural complications Fall	7.0% 28/402 • Number of events 42 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Fatigue	16.2% 65/402 • Number of events 86 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Headache	21.4% 86/402 • Number of events 135 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Herpes simplex	10.9% 44/402 • Number of events 70 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Herpes zoster	6.0% 24/402 • Number of events 27 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Vascular disorders Hypertension	19.4% 78/402 • Number of events 94 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Influenza	10.0% 40/402 • Number of events 56 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Psychiatric disorders Insomnia	9.0% 36/402 • Number of events 44 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Joint swelling	5.2% 21/402 • Number of events 39 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Lower respiratory tract infection	6.7% 27/402 • Number of events 65 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Muscle spasms	6.7% 27/402 • Number of events 34 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Nasopharyngitis	35.1% 141/402 • Number of events 380 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Nausea	12.2% 49/402 • Number of events 65 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Neck pain	5.5% 22/402 • Number of events 26 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
General disorders Oedema peripheral	9.5% 38/402 • Number of events 54 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Osteoarthritis	6.5% 26/402 • Number of events 49 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Pain in extremity	11.4% 46/402 • Number of events 68 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Paraesthesia	5.7% 23/402 • Number of events 29 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Pharyngitis	5.2% 21/402 • Number of events 36 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Respiratory, thoracic and mediastinal disorders Pharyngolaryngeal pain	9.5% 38/402 • Number of events 52 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Skin and subcutaneous tissue disorders Rash	16.4% 66/402 • Number of events 104 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Musculoskeletal and connective tissue disorders Rheumatoid arthritis	15.7% 63/402 • Number of events 109 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Nervous system disorders Sciatica	7.0% 28/402 • Number of events 34 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Sinusitis	18.4% 74/402 • Number of events 123 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Upper respiratory tract infection	23.1% 93/402 • Number of events 198 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Urinary tract infection	20.9% 84/402 • Number of events 159 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Infections and infestations Viral infection	6.7% 27/402 • Number of events 42 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.
Gastrointestinal disorders Vomiting	9.2% 37/402 • Number of events 58 • Adverse Events (AEs) were collected over the whole Study Period of 8 Years from first dose of study medication (Baseline of feeder study or First Visit of this study for subjects randomized to Placebo) to 24 Weeks post last dose (Last Follow-up Visit). AEs refer to the Safety Set (SS). SS includes all of the 402 enrolled subjects.

Additional Information

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Restriction type: GT60