Trial Outcomes & Findings for Long-Term Safety and Tolerability Study of NKTR-181 in Subjects With Chronic Low Back Pain or Chronic Non-Cancer Pain (NCT NCT02367820)

NCT ID: NCT02367820

Last Updated: 2021-06-22

Results Overview

Count of subjects reporting treatment emergent adverse events

Recruitment status

COMPLETED

Study phase

PHASE3

Target enrollment

638 participants

Primary outcome timeframe

Screening baseline through end of study, an average of 57 weeks

Results posted on

2021-06-22

Participant Flow

First subject screened 14 April 2015. Last subject out: 24 January 2018. The study was conducted at 55 medical/research centers in the United States.

The titration phase of the study was designed to titrate patients to a dose of NKTR-181 that provided adequate analgesia and acceptable side effects.

Participant milestones

Participant milestones
Measure	NKTR-181 NKTR-181 tablets at 100-600 mg orally twice daily
Overall Study STARTED	638
Overall Study COMPLETED	402
Overall Study NOT COMPLETED	236

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

Long-Term Safety and Tolerability Study of NKTR-181 in Subjects With Chronic Low Back Pain or Chronic Non-Cancer Pain

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	Rollover NKTR-181 n=214 Participants Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=217 Participants Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Naive n=73 Participants Newly enrolled opioid naïve subjects	De Novo Opioid Experienced n=134 Participants Newly enrolled opioid experienced subjects	Total n=638 Participants Total of all reporting groups
Age, Continuous	51.7 Years STANDARD_DEVIATION 12.01 • n=5 Participants	51.4 Years STANDARD_DEVIATION 12.31 • n=7 Participants	51.9 Years STANDARD_DEVIATION 10.44 • n=5 Participants	55.6 Years STANDARD_DEVIATION 11.12 • n=4 Participants	52.4 Years STANDARD_DEVIATION 11.85 • n=21 Participants
Sex: Female, Male Female	123 Participants n=5 Participants	126 Participants n=7 Participants	44 Participants n=5 Participants	82 Participants n=4 Participants	375 Participants n=21 Participants
Sex: Female, Male Male	91 Participants n=5 Participants	91 Participants n=7 Participants	29 Participants n=5 Participants	52 Participants n=4 Participants	263 Participants n=21 Participants
Race (NIH/OMB) American Indian or Alaska Native	3 Participants n=5 Participants	2 Participants n=7 Participants	0 Participants n=5 Participants	1 Participants n=4 Participants	6 Participants n=21 Participants
Race (NIH/OMB) Asian	2 Participants n=5 Participants	2 Participants n=7 Participants	1 Participants n=5 Participants	0 Participants n=4 Participants	5 Participants n=21 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants n=5 Participants	1 Participants n=7 Participants	0 Participants n=5 Participants	0 Participants n=4 Participants	1 Participants n=21 Participants
Race (NIH/OMB) Black or African American	71 Participants n=5 Participants	70 Participants n=7 Participants	19 Participants n=5 Participants	24 Participants n=4 Participants	184 Participants n=21 Participants
Race (NIH/OMB) White	136 Participants n=5 Participants	138 Participants n=7 Participants	51 Participants n=5 Participants	106 Participants n=4 Participants	431 Participants n=21 Participants
Race (NIH/OMB) More than one race	0 Participants n=5 Participants	1 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	3 Participants n=21 Participants
Race (NIH/OMB) Unknown or Not Reported	2 Participants n=5 Participants	3 Participants n=7 Participants	1 Participants n=5 Participants	2 Participants n=4 Participants	8 Participants n=21 Participants

PRIMARY outcome

Timeframe: Screening baseline through end of study, an average of 57 weeks

Count of subjects reporting treatment emergent adverse events

Outcome measures

Outcome measures
Measure	Rollover NKTR-181 n=214 Participants Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=217 Participants Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Opioid Experienced n=134 Participants Newly enrolled opioid experienced subjects	De Novo Naive n=73 Participants Newly enrolled opioid naïve subjects
Number of Participants Reporting Adverse Events	138 Participants	151 Participants	110 Participants	62 Participants

SECONDARY outcome

Timeframe: Baseline, monthly change from baseline till the end of study

Population: Safety Analysis Set is defined as all enrolled subjects who received at least 1 dose of study drug.

A self-reported scale measuring severity of pain on function. The mean of the 4 intensity items (3-6) is calculated and used as a measure of pain severity. If there were missing items when the pain severity score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain intensity and interference for each question is from 0 to 10. The range of possible scores is from 0 to 70. Higher score indicates relatively worse pain severity and greater interference that pain causes in day to day activities.

Outcome measures

Outcome measures
Measure	Rollover NKTR-181 n=185 Participants Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=188 Participants Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Opioid Experienced n=129 Participants Newly enrolled opioid experienced subjects	De Novo Naive n=72 Participants Newly enrolled opioid naïve subjects
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Baseline	3.57 Scores on a scale Standard Deviation 1.968	4.11 Scores on a scale Standard Deviation 2.112	5.91 Scores on a scale Standard Deviation 1.749	6.18 Scores on a scale Standard Deviation 1.459
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 60	-1.28 Scores on a scale Standard Deviation 2.037	-1.58 Scores on a scale Standard Deviation 2.172	-2.01 Scores on a scale Standard Deviation 2.000	-2.49 Scores on a scale Standard Deviation 1.966
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 180	-1.37 Scores on a scale Standard Deviation 2.103	-1.49 Scores on a scale Standard Deviation 2.425	-1.87 Scores on a scale Standard Deviation 2.053	-2.80 Scores on a scale Standard Deviation 2.173
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 1	-1.22 Scores on a scale Standard Deviation 2.109	-1.71 Scores on a scale Standard Deviation 2.212	-2.19 Scores on a scale Standard Deviation 2.009	-2.66 Scores on a scale Standard Deviation 1.808
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 30	-1.02 Scores on a scale Standard Deviation 2.233	-1.40 Scores on a scale Standard Deviation 2.314	-2.26 Scores on a scale Standard Deviation 2.134	-2.26 Scores on a scale Standard Deviation 2.068
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 90	-1.31 Scores on a scale Standard Deviation 2.142	-1.48 Scores on a scale Standard Deviation 2.278	-2.06 Scores on a scale Standard Deviation 1.932	-2.38 Scores on a scale Standard Deviation 2.115
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 120	-1.24 Scores on a scale Standard Deviation 2.269	-1.44 Scores on a scale Standard Deviation 2.267	-2.04 Scores on a scale Standard Deviation 1.933	-2.58 Scores on a scale Standard Deviation 1.874
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 150	-1.28 Scores on a scale Standard Deviation 2.116	-1.54 Scores on a scale Standard Deviation 2.319	-2.09 Scores on a scale Standard Deviation 2.016	-2.44 Scores on a scale Standard Deviation 2.323
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 210	-1.28 Scores on a scale Standard Deviation 2.131	-1.58 Scores on a scale Standard Deviation 2.220	-2.06 Scores on a scale Standard Deviation 1.944	-3.01 Scores on a scale Standard Deviation 2.258
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 240	-1.15 Scores on a scale Standard Deviation 1.837	-1.82 Scores on a scale Standard Deviation 2.190	-2.21 Scores on a scale Standard Deviation 1.908	-2.84 Scores on a scale Standard Deviation 2.289
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 270	-1.45 Scores on a scale Standard Deviation 2.154	-1.62 Scores on a scale Standard Deviation 2.366	-1.83 Scores on a scale Standard Deviation 1.915	-2.65 Scores on a scale Standard Deviation 1.933
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 300	-1.09 Scores on a scale Standard Deviation 2.149	-1.48 Scores on a scale Standard Deviation 2.303	-2.08 Scores on a scale Standard Deviation 2.144	-2.31 Scores on a scale Standard Deviation 2.043
Change From Baseline in Brief Pain Inventory (BPI) Pain Intensity Item to Week 52 Pain Intensity: Change from Baseline to Day 364	-0.78 Scores on a scale Standard Deviation 2.175	-1.31 Scores on a scale Standard Deviation 2.520	-1.20 Scores on a scale Standard Deviation 2.102	-2.15 Scores on a scale Standard Deviation 2.055

SECONDARY outcome

Timeframe: Baseline, monthly change from baseline till the end of study

Population: Safety Analysis Set is defined as all enrolled subjects who received at least 1 dose of study drug.

A self-reported scale measuring interference of pain on function. The mean of the 7 interference items was calculated and used as a measure of Pain interference. If there were missing items when the pain interference score was calculated, the mean of the completed items in one dimension (dimensions include pain severity and pain interference) were imputed to substitute the missing item, provided that more than 50% of the items in one dimension were completed (Halling, 1999). The range of pain interference is from 0 to 10. Higher score indicates relatively worse pain problem.

Outcome measures

Outcome measures
Measure	Rollover NKTR-181 n=185 Participants Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=188 Participants Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Opioid Experienced n=129 Participants Newly enrolled opioid experienced subjects	De Novo Naive n=72 Participants Newly enrolled opioid naïve subjects
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 1	-1.23 Scores on a scale Standard Deviation 2.301	-1.52 Scores on a scale Standard Deviation 2.163	-2.34 Scores on a scale Standard Deviation 2.175	-2.71 Scores on a scale Standard Deviation 2.169
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 30	-1.07 Scores on a scale Standard Deviation 2.070	-1.29 Scores on a scale Standard Deviation 2.340	-2.51 Scores on a scale Standard Deviation 2.583	-2.17 Scores on a scale Standard Deviation 2.679
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 60	-1.17 Scores on a scale Standard Deviation 2.070	-1.32 Scores on a scale Standard Deviation 2.104	-2.18 Scores on a scale Standard Deviation 2.350	-2.38 Scores on a scale Standard Deviation 2.277
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 90	-1.24 Scores on a scale Standard Deviation 2.344	-1.34 Scores on a scale Standard Deviation 2.222	-2.15 Scores on a scale Standard Deviation 2.447	-2.11 Scores on a scale Standard Deviation 2.179
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 120	-1.31 Scores on a scale Standard Deviation 2.389	-1.36 Scores on a scale Standard Deviation 2.309	-2.33 Scores on a scale Standard Deviation 2.299	-2.48 Scores on a scale Standard Deviation 2.173
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 150	-1.12 Scores on a scale Standard Deviation 2.329	-1.22 Scores on a scale Standard Deviation 2.500	-2.26 Scores on a scale Standard Deviation 2.372	-2.16 Scores on a scale Standard Deviation 2.290
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 180	-1.31 Scores on a scale Standard Deviation 2.247	-1.33 Scores on a scale Standard Deviation 2.507	-2.09 Scores on a scale Standard Deviation 2.551	-2.27 Scores on a scale Standard Deviation 2.404
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 210	-0.95 Scores on a scale Standard Deviation 2.325	-1.29 Scores on a scale Standard Deviation 2.215	-2.43 Scores on a scale Standard Deviation 2.365	-2.38 Scores on a scale Standard Deviation 2.611
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 240	-0.95 Scores on a scale Standard Deviation 2.119	-1.55 Scores on a scale Standard Deviation 2.197	-2.49 Scores on a scale Standard Deviation 2.503	-2.27 Scores on a scale Standard Deviation 2.240
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 270	-1.21 Scores on a scale Standard Deviation 2.339	-1.37 Scores on a scale Standard Deviation 2.329	-2.02 Scores on a scale Standard Deviation 2.374	-2.01 Scores on a scale Standard Deviation 2.193
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 300	-0.90 Scores on a scale Standard Deviation 2.307	-1.38 Scores on a scale Standard Deviation 2.137	-2.07 Scores on a scale Standard Deviation 2.280	-1.94 Scores on a scale Standard Deviation 2.357
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Change from Baseline to Day 364	-0.69 Scores on a scale Standard Deviation 2.258	-1.14 Scores on a scale Standard Deviation 2.493	-1.33 Scores on a scale Standard Deviation 2.396	-2.08 Scores on a scale Standard Deviation 2.504
Change From Baseline in Brief Pain Inventory (BPI) Pain Interference Item to Week 52 Pain Interference: Baseline	2.91 Scores on a scale Standard Deviation 2.205	3.25 Scores on a scale Standard Deviation 2.281	5.41 Scores on a scale Standard Deviation 2.298	5.44 Scores on a scale Standard Deviation 1.957

Adverse Events

Rollover NKTR-181

Serious events: 10 serious events

Other events: 136 other events

Deaths: 0 deaths

Rollover PBO

Serious events: 8 serious events

Other events: 151 other events

Deaths: 0 deaths

De Novo Opioid Experienced

Serious events: 8 serious events

Other events: 110 other events

Deaths: 0 deaths

De Novo Naive

Serious events: 4 serious events

Other events: 62 other events

Deaths: 0 deaths

Serious adverse events

Other adverse events

Additional Information

Medical Affairs

Nektar Therapeutics

Phone: 855-482-8676

Email: [email protected]

Results disclosure agreements

Principal investigator is a sponsor employee If a joint manuscript has not been submitted for publication within twelve (12) months of completion or termination of the study, the PI is free to publish separately, upon provision of any proposed publication or manuscript to the Sponsor at least sixty (60) days before it is submitted or otherwise disclosed.
Publication restrictions are in place

Restriction type: OTHER

Serious adverse events
Measure	Rollover NKTR-181 n=214 participants at risk Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=217 participants at risk Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Opioid Experienced n=134 participants at risk Newly enrolled opioid experienced subjects	De Novo Naive n=73 participants at risk Newly enrolled opioid naïve subjects
Cardiac disorders Myocardial Infarction	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Endocrine disorders Goitre	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders abdominal pain	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Diarrhoea	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Duodenal ulcer	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Duodenitis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 1/73 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Gastric ulcer	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Pancreatitis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 1/73 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Rectal haemorrhage	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
General disorders Generalized Oedema	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 1/73 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Gastroenteritis	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Pneumonia	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Cellulitis	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Diverticulitis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Hisoplasmosis	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Urinary Tract Infection	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Injury, poisoning and procedural complications Head injury	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Injury, poisoning and procedural complications Road traffic accident	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Injury, poisoning and procedural complications Subdural haematoma	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Musculoskeletal and connective tissue disorders Back Pain	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Musculoskeletal and connective tissue disorders Osteoarthritis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 1/73 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Follicular thyroid cancer	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Neoplasms benign, malignant and unspecified (incl cysts and polyps) Lung adenocarcinoma	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Cerebral Infarction	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Cerebrovascular accident	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Convulsion	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Syncope	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Renal and urinary disorders Renal Mass	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Reproductive system and breast disorders Uterine Cyst	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Respiratory, thoracic and mediastinal disorders Chronic Obstructive Pulmonary Disease	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 1/73 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Respiratory, thoracic and mediastinal disorders Pulmonary fibrosis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Skin and subcutaneous tissue disorders Decubitus Ulcer	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Vascular disorders Deep Vein Thrombosis	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/217 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.75% 1/134 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Vascular disorders Malignant hypertension	0.00% 0/214 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.46% 1/217 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/134 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	0.00% 0/73 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.

Other adverse events
Measure	Rollover NKTR-181 n=214 participants at risk Subjects administered NKTR-181 in preceding phase 3 efficacy/safety study	Rollover PBO n=217 participants at risk Subjects administered placebo in preceding phase 3 efficacy/safety study	De Novo Opioid Experienced n=134 participants at risk Newly enrolled opioid experienced subjects	De Novo Naive n=73 participants at risk Newly enrolled opioid naïve subjects
Gastrointestinal disorders Constipation	13.1% 28/214 • Number of events 28 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	18.9% 41/217 • Number of events 41 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	41.8% 56/134 • Number of events 56 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	56.2% 41/73 • Number of events 41 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Nausea	7.9% 17/214 • Number of events 17 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	9.7% 21/217 • Number of events 21 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	12.7% 17/134 • Number of events 17 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	28.8% 21/73 • Number of events 21 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Diarrhoea	2.8% 6/214 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	5.1% 11/217 • Number of events 11 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.0% 4/134 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	11.0% 8/73 • Number of events 8 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Gastrointestinal disorders Vomiting	6.1% 13/214 • Number of events 13 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.6% 10/217 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	2.2% 3/134 • Number of events 3 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	12.3% 9/73 • Number of events 9 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
General disorders Drug withdrawal	4.7% 10/214 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	7.4% 16/217 • Number of events 16 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	7.5% 10/134 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	2.7% 2/73 • Number of events 2 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
General disorders Fatigue	0.47% 1/214 • Number of events 1 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.8% 4/217 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.0% 4/134 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	5.5% 4/73 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Upper respiratory tract infection	5.6% 12/214 • Number of events 12 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	8.8% 19/217 • Number of events 19 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	7.5% 10/134 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	9.6% 7/73 • Number of events 7 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Urinary tract infection	4.7% 10/214 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	6.5% 14/217 • Number of events 14 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.7% 5/134 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	8.2% 6/73 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Infections and infestations Influenza	2.3% 5/214 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.6% 10/217 • Number of events 10 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.0% 4/134 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	6.8% 5/73 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Musculoskeletal and connective tissue disorders Arthralgia	2.8% 6/214 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.2% 7/217 • Number of events 7 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	5.2% 7/134 • Number of events 7 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.1% 3/73 • Number of events 3 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Headache	4.2% 9/214 • Number of events 9 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	9.7% 21/217 • Number of events 21 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	15.7% 21/134 • Number of events 21 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	8.2% 6/73 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Somnolence	2.8% 6/214 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	6.0% 13/217 • Number of events 13 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	6.7% 9/134 • Number of events 9 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.1% 3/73 • Number of events 3 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Nervous system disorders Dizziness	2.3% 5/214 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.4% 3/217 • Number of events 3 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.5% 6/134 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	6.8% 5/73 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Psychiatric disorders Insomnia	1.9% 4/214 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	1.8% 4/217 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	3.7% 5/134 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	5.5% 4/73 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.
Skin and subcutaneous tissue disorders Pruritis	1.9% 4/214 • Number of events 4 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	2.3% 5/217 • Number of events 5 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	4.5% 6/134 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.	8.2% 6/73 • Number of events 6 • Adverse events were reported starting immediately after the subject provided written informed consent through the end of study, which was approximately 57-weeks in length for each subject. Adverse events were collected after the subject provided written informed consent through the end of study. Adverse event data were obtained via spontaneous reports or per direct questioning or observation during protocol-mandated study assessments. All ongoing AEs were followed until resolution or for 14 days after the subject's last visit, whichever came first. All SAEs were followed until resolution, stabilization of condition, return to baseline, or until follow-up was no longer possible.