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Clinical Trial Results:
A Double Blind, Randomized, Placebo Controlled, Parallel Group Study to Simultaneously Qualify a Biomarker Algorithm for Prognosis of Risk of Developing Mild Cognitive Impairment due to Alzheimer’s Disease (MCI due to AD) and to Test the Safety and Efficacy of Pioglitazone (AD-4833 SR 0.8 mg QD) to Delay the Onset of MCI due to AD in Cognitively Normal Subjects

Summary
EudraCT number	2012-003111-58
Trial protocol	GB IT DE
Global end of trial date	06 Sep 2018

Results information
Results version number	v1(current)
This version publication date	07 Aug 2019
First version publication date	07 Aug 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

Collapse all Expand all

Trial information

Top of page

Sponsor protocol code

AD-4833/TOMM40_301

ISRCTN number

-

US NCT number

NCT01931566

WHO universal trial number (UTN)

U1111-1139-0355

Sponsor organisation name

Takeda Development Center Americas, Inc.

Sponsor organisation address

One Takeda Parkway, Deerfield, IL, United States, 60015

Public contact

Medical Director, Clinical Science, Takeda Development Center Americas, Inc., +1 877-825-3327, clinicaltrialregistry@tpna.com

Scientific contact

Medical Director, Clinical Science, Takeda Development Center Americas, Inc., +1 877-825-3327, clinicaltrialregistry@tpna.com

Is trial part of an agreed paediatric investigation plan (PIP)

No

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

No

Analysis stage

Final

Date of interim/final analysis

06 Sep 2018

Is this the analysis of the primary completion data?

No

Global end of trial reached?

Yes

Global end of trial date

06 Sep 2018

Was the trial ended prematurely?

Yes

Main objective of the trial

The purpose of this study is to qualify the biomarker risk algorithm composed of TOMM40 rs10524523 genotype, apolipoprotein E (APOE) genotype, and age for prognosis of the risk of developing mild cognitive impairment (MCI) due to Alzheimer’s Disease (AD) within 5 years; and to evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI due to AD in cognitively-normal subjects who are at high-risk, as identified by the biomarker risk algorithm at enrollment, for developing MCI due to AD within 5 years.

Protection of trial subjects

All study participants were required to read and sign an Informed Consent Form.

Background therapy

-

Evidence for comparator

-

Actual start date of recruitment

01 Aug 2013

Long term follow-up planned

No

Independent data monitoring committee (IDMC) involvement?

Yes

Number of subjects enrolled per country

Country: Number of subjects enrolled

Australia: 489

Country: Number of subjects enrolled

Germany: 21

Country: Number of subjects enrolled

Switzerland: 39

Country: Number of subjects enrolled

United Kingdom: 728

Country: Number of subjects enrolled

United States: 2217

Worldwide total number of subjects

3494

EEA total number of subjects

749

Number of subjects enrolled per age group

In utero

0

Preterm newborn - gestational age < 37 wk

0

Newborns (0-27 days)

0

Infants and toddlers (28 days-23 months)

0

Children (2-11 years)

0

Adolescents (12-17 years)

0

Adults (18-64 years)

0

From 65 to 84 years

3494

85 years and over

0

Subject disposition

Top of page

Recruitment details

Participants took part in the study at 57 investigative sites in United States, United Kingdom, Germany, Australia, and Switzerland from 01 Aug 2013 to 06 Sep 2018.

Screening details

Participants with a diagnosis of MCI due to AD were enrolled to receive either pioglitazone (0.8 mg sustained release tablet) or placebo.

Period 1 title

Overall Study (overall period)

Is this the baseline period?

Yes

Allocation method

Non-randomised - controlled

Blinding used

Double blind

Roles blinded

Investigator, Monitor, Carer, Data analyst, Subject

Are arms mutually exclusive

Yes

Low Risk Placebo

Arm description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pioglitazone placebo-matching tablets

High Risk Placebo

Arm description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Arm type

Placebo

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pioglitazone placebo-matching tablets

High Risk Pioglitazone

Arm description

Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Arm type

Experimental

Investigational medicinal product name

Pioglitazone

Investigational medicinal product code

Other name

AD-4833

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Pioglitazone tablets

Number of subjects in period 1	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone
Started	433	1516	1545
Treated	423	1467	1491
Completed	4	40	39
Not completed	429	1476	1506
Major Protocol Deviation	5	14	21
Study Termination	289	968	1037
Adverse event, non-fatal	37	167	132
Voluntary Withdrawal	78	245	225
Reason Not Specified	11	47	53
Randomized But Not Treated	6	9	14
Lost to follow-up	3	26	23
Missing	-	-	1

Baseline characteristics

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Reporting group title

Low Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Pioglitazone

Reporting group description

Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Reporting group values	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone	Total
Number of subjects	433	1516	1545	3494
Age, Customized
Units: Subjects
<75 years	360	632	658	1650
>=75 years	73	884	887	1844
Age Continuous
Units: years
arithmetic mean (standard deviation)	70.3 ( 4.02 )	74.6 ( 5.27 )	74.4 ( 5.25 )	-
Sex: Female, Male
Units: Subjects
Female	259	850	812	1921
Male	174	666	733	1573
Ethnicity (NIH/OMB)
Units: Subjects
Hispanic or Latino	8	19	12	39
Not Hispanic or Latino	425	1497	1533	3455
Unknown or Not Reported	0	0	0	0
Race/Ethnicity, Customized
Units: Subjects
American Indian or Alaska Native	0	0	4	4
Asian	1	10	14	25
Black or African American	10	38	39	87
Native Hawaiian or Other Pacific Islander	0	1	1	2
White	421	1463	1484	3368
Multiracial	1	4	3	8
Race/Ethnicity, Customized
Units: Subjects
Non-Hispanic/Latino Caucasian	413	1444	1472	3329
Hispanic/Latino and/or non-Caucasian	20	72	73	165
Region of Enrollment
Units: Subjects
United States\|	270	962	985	2217
United Kingdom\|	102	311	315	728
Australia\|	56	215	218	489
Switzerland\|	3	18	18	39
Germany\|	2	10	9	21

End points

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Reporting group title

Low Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Pioglitazone

Reporting group description

Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Primary: Time to Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for Placebo-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, Low-risk, Non-Hispanic/Latino Caucasian Participants

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End point title

Time to Diagnosis of Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) for Placebo-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, Low-risk, Non-Hispanic/Latino Caucasian Participants ^[1]

End point description

The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time. Full Analysis Set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who did not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.

End point type

Primary

End point timeframe

Baseline to the end of study (approximately up to 5 years)

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned in the participants who received a placebo.

End point values	Low Risk Placebo	High Risk Placebo
Number of subjects analysed	402	1406
Units: days
arithmetic mean (full range (min-max))	905.44 (189.00 to 909.00)	1238.67 (168.00 to 1268.00)

Statistical Analysis 1

Comparison groups

Low Risk Placebo v High Risk Placebo

Number of subjects included in analysis

1808

Analysis specification

Pre-specified

Analysis type

P-value

= 0.016 ^[2]

Method

Weighted Generalized Log Rank Test

Confidence interval

Notes
[2] - P-value comparing high risk to low risk placebo was obtained using weighted generalized log-rank test stratified by gender as nonparametric analysis.

Primary: Time to Diagnosis of MCI due to AD for Pioglitazone-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, High-risk, Non-Hispanic/Latino, Caucasian Participants

Top of page

End point title

Time to Diagnosis of MCI due to AD for Pioglitazone-treated, High-risk, Non-Hispanic/Latino Caucasian Participants versus Placebo-treated, High-risk, Non-Hispanic/Latino, Caucasian Participants ^[3]

End point description

The event definition for MCI-AD was the time in days from the randomization date to the date of the first of two consecutive scheduled visits at which a participant was assessed with a diagnosis of MCI due to AD confirmed by adjudication committee. Here, the time to event was reported as the restricted mean survival time. The restricted mean survival time was defined as the area under the curve of the survival function up to the largest event time. FAS included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who did not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.

End point type

Primary

End point timeframe

Baseline to the end of study (approximately up to 5 years)

Notes
[3] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned in the High-risk stratum of participants.

End point values	High Risk Placebo	High Risk Pioglitazone
Number of subjects analysed	1406	1430
Units: days
arithmetic mean (full range (min-max))	1238.67 (168.00 to 1268.00)	1261.24 (168.00 to 1285.00)

Statistical Analysis 1

Comparison groups

High Risk Placebo v High Risk Pioglitazone

Number of subjects included in analysis

2836

Analysis specification

Pre-specified

Analysis type

P-value

= 0.314 ^[4]

Method

Weighted Generalized Log Rank Test

Confidence interval

Notes
[4] - P-value comparing active to placebo was obtained using the weighted generalized log-rank test stratified by gender as a nonparametric analysis.

Secondary: Change from Baseline for Cognitive Decline on Composite Score on the Cognitive Test Battery for Pioglitazone-treated Participants versus Placebo-treated Participants in the High-risk Stratum

Top of page

End point title

Change from Baseline for Cognitive Decline on Composite Score on the Cognitive Test Battery for Pioglitazone-treated Participants versus Placebo-treated Participants in the High-risk Stratum ^[5]

End point description

Composite scores derived from the test battery. Domains of Episodic Memory [California Verbal Learning Test-2nd Edition (CVLT-II), Brief Visuospatial Memory Test-Revised (BVMT-R)]; Executive Function [Trail Making Test (TMT) (Part B), Wechsler Adult Intelligence Scale (WAIS)-III Digit Span Test-backwards span]; Language [Multilingual Naming Test (MiNT), Semantic Fluency (animals), Lexical/phonemic fluency (F, A, and S in English; D, S, and F in German)]; and Attention [WAIS-III Digit Span Test-forward span, TMT (Part A)] used for composite score. 12 measures were derived from 8 neuropsychological tests. CVLT-II test involved 2 primary measures (short, long delay recall); BVMT-R had 2 measures (copy and recall); Digit Span and Trail both had 2 measures (forward and backward span and Parts A and B). There was 1 total score for each test: CDT, MINT, semantic and lexical fluency. Total score ranged from -1.222 to 1.707 at baselinbe, a higher composite score indicated better cognition.

End point type

Secondary

End point timeframe

Baseline and Months 6, 12, 18, 24, 30, 36, 42 and 48

Notes
[5] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned in the High-risk stratum of participants.

End point values	High Risk Placebo	High Risk Pioglitazone
Number of subjects analysed	1406	1430
Units: score on a scale
arithmetic mean (standard deviation)
Change at Month 6\|	0.0186 ( 0.30742 )	0.0338 ( 0.29547 )
Change at Month 12\|	0.0682 ( 0.30721 )	0.0904 ( 0.29531 )
Change at Month 18\|	0.0752 ( 0.31077 )	0.0892 ( 0.30919 )
Change at Month 24\|	0.1005 ( 0.31814 )	0.1189 ( 0.30424 )
Change at Month 30\|	0.1202 ( 0.33480 )	0.1297 ( 0.31836 )
Change at Month 36\|	0.1507 ( 0.32076 )	0.1436 ( 0.31619 )
Change at Month 42\|	0.1501 ( 0.32423 )	0.0973 ( 0.32720 )
Change at Month 48\|	0.1841 ( 0.27508 )	0.1687 ( 0.40621 )

No statistical analyses for this end point

Secondary: Change from Baseline in Instrumental Activities of Daily Living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between Pioglitazone-treated and Placebo-treated Groups of the High-risk Stratum

Top of page

End point title

Change from Baseline in Instrumental Activities of Daily Living (Alzheimer's Disease Cooperative Study Activities of Daily Living - Prevention Instrument [ADCS ADL-PI]) between Pioglitazone-treated and Placebo-treated Groups of the High-risk Stratum ^[6]

End point description

The ADCS ADL-PI is a functional measure that was specifically designed for standardized administration over long duration clinical studies to prevent AD. The ADCS ADL-PI is a 20-item instrument that included 15 ADL questions, which were scored as 1 (with a lot of difficulty), 2 (with some difficulty), or 3 (as well as usually, with no difficulty), plus 5 vision, hearing, and mobility questions, which were scored from 0 (no) to 1 (yes). ADL Total ranged from 0 to 45, and lower scores indicated greater disability. Full Analysis Set (FAS) included all participants who were randomized, received at least 1 dose of study drug, and at least 1 valid postbaseline value for assessment of primary efficacy. A participant who does not have an event of MCI due to AD was censored at the date of the last visit at which MCI due to AD could have been assessed.

End point type

Secondary

End point timeframe

Baseline and Months 6, 12, 18, 24, 30, 36, 42 and 48

Notes
[6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: This endpoint was planned in the High-risk stratum of participants.

End point values	High Risk Placebo	High Risk Pioglitazone
Number of subjects analysed	1406	1430
Units: score on a scale
arithmetic mean (standard deviation)
Change at Month 6\|	0.1 ( 3.54 )	0.1 ( 3.50 )
Change at Month 12\|	0.0 ( 3.99 )	0.1 ( 3.95 )
Change at Month 18\|	0.1 ( 3.87 )	0.2 ( 3.59 )
Change at Month 24\|	0.3 ( 3.78 )	0.2 ( 3.63 )
Change at Month 30\|	0.3 ( 3.76 )	0.1 ( 3.61 )
Change at Month 36\|	0.2 ( 3.77 )	0.2 ( 3.72 )
Change at Month 42\|	0.3 ( 3.63 )	0.3 ( 3.74 )
Change at Month 48\|	0.1 ( 4.93 )	0.3 ( 5.32 )

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Baseline up to 30 days after the last dose of study drug (up to 935 days)

Adverse event reporting additional description

At each visit the investigator had to document any occurrence of adverse events and abnormal laboratory findings. Any event spontaneously reported by the participant or observed by the investigator was recorded, irrespective of the relation to study treatment.

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Low Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Placebo

Reporting group description

Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Reporting group title

High Risk Pioglitazone

Reporting group description

Pioglitazone 0.8 mg, sustained release (SR) tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years.

Serious adverse events	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone
Total subjects affected by serious adverse events
subjects affected / exposed	81 / 427 (18.97%)	404 / 1507 (26.81%)	358 / 1531 (23.38%)
number of deaths (all causes)	2	21	7
number of deaths resulting from adverse events
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Prostate cancer
subjects affected / exposed	1 / 427 (0.23%)	8 / 1507 (0.53%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	1 / 1	0 / 8	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer
subjects affected / exposed	2 / 427 (0.47%)	2 / 1507 (0.13%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatic carcinoma
Additional description: One treatment-emergent death occurred during treatment with placebo (in low-risk group) and was not related. Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 2	0 / 0
Malignant melanoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	2 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder transitional cell carcinoma
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diffuse large B-cell lymphoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive ductal breast carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung neoplasm malignant
subjects affected / exposed	1 / 427 (0.23%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma of colon
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adenocarcinoma pancreas
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial cancer
subjects affected / exposed	2 / 427 (0.47%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lymphoma
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Malignant melanoma in situ
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parathyroid tumour benign
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal adenocarcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of lung
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Anal squamous cell carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Basal cell carcinoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign neoplasm of thyroid gland
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Benign renal neoplasm
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bladder cancer stage 0, with cancer in situ
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	1 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Brain neoplasm
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Breast cancer in situ
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac myxoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangiocarcinoma
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Choroid plexus papilloma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colon cancer stage II
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endometrial adenocarcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Follicular thyroid cancer
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal carcinoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Glioma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial meningioma malignant
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Invasive papillary breast carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine benign neoplasm
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal squamous cell carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung adenocarcinoma stage II
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung cancer metastatic
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Lung carcinoma cell type unspecified stage IV
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mantle cell lymphoma recurrent
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metastatic malignant melanoma
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mucinous breast carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myelodysplastic syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-Hodgkin's lymphoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-small cell lung cancer stage IIIB
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal adenocarcinoma
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Oesophageal carcinoma
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Oesophageal squamous cell carcinoma
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ovarian adenoma
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Papillary cystadenoma lymphomatosum
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Penile squamous cell carcinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pituitary tumour benign
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plasma cell myeloma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Plasmacytoma
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Polycythaemia vera
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal cancer
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal cancer
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Schwannoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord neoplasm
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of skin
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Squamous cell carcinoma of the tongue
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tongue neoplasm malignant stage unspecified
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tonsil cancer
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine cancer
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine leiomyoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Deep vein thrombosis
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypotension
Additional description: One treatment-emergent death occurred during treatment with placebo (in low-risk group) and was not related.
subjects affected / exposed	1 / 427 (0.23%)	4 / 1507 (0.27%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 1	0 / 0	0 / 0
Aortic stenosis
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aortic aneurysm
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertension
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery occlusion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral artery stenosis
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Peripheral vascular disorder
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Varicose vein
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypertensive crisis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Orthostatic hypotension
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Superior mesenteric artery syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Superior vena cava syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Surgical and medical procedures
Shoulder arthroplasty
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Non-cardiac chest pain
subjects affected / exposed	0 / 427 (0.00%)	5 / 1507 (0.33%)	8 / 1531 (0.52%)
occurrences causally related to treatment / all	0 / 0	0 / 5	0 / 8
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Asthenia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest pain
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hernia
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyrexia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Adverse drug reaction
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Death
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Fatigue
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ill-defined disorder
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Systemic inflammatory response syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Unevaluable event
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Immune system disorders
Anaphylactic reaction
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug hypersensitivity
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sarcoidosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Benign prostatic hyperplasia
subjects affected / exposed	2 / 427 (0.47%)	4 / 1507 (0.27%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatomegaly
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vaginal prolapse
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acquired hydrocele
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Prostatic haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterine prolapse
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Uterovaginal prolapse
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vaginal haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Pulmonary embolism
subjects affected / exposed	1 / 427 (0.23%)	9 / 1507 (0.60%)	11 / 1531 (0.72%)
occurrences causally related to treatment / all	0 / 1	0 / 9	0 / 12
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary hypertension
subjects affected / exposed	2 / 427 (0.47%)	6 / 1507 (0.40%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 2	0 / 6	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic obstructive pulmonary disease
subjects affected / exposed	0 / 427 (0.00%)	4 / 1507 (0.27%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 6	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspnoea
subjects affected / exposed	1 / 427 (0.23%)	2 / 1507 (0.13%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary fibrosis
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Asthma
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumothorax
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory failure
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Acute respiratory failure
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiectasis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cough
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Interstitial lung disease
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pleural effusion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary oedema
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Idiopathic pulmonary fibrosis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lung disorder
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pulmonary granuloma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Psychiatric disorders
Mental status changes
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol abuse
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Alcohol withdrawal syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Confusional state
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Delirium
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Panic attack
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Suicidal ideation
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Product issues
Device dislocation
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholecystitis
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	6 / 1531 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis acute
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholelithiasis
subjects affected / exposed	2 / 427 (0.47%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 2	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bile duct stone
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholangitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cholecystitis chronic
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Drug-induced liver injury
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaundice
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Primary biliary cholangitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Investigations
Blood magnesium decreased
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood pressure increased
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Electrocardiogram QT prolonged
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	1 / 1	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood parathyroid hormone increased
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Heart rate irregular
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatic enzyme increased
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Platelet count decreased
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	1 / 427 (0.23%)	7 / 1507 (0.46%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 2	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hip fracture
subjects affected / exposed	2 / 427 (0.47%)	7 / 1507 (0.46%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 2	0 / 8	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib fracture
subjects affected / exposed	0 / 427 (0.00%)	4 / 1507 (0.27%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femur fracture
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subarachnoid haemorrhage
Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
subjects affected / exposed	0 / 427 (0.00%)	4 / 1507 (0.27%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Upper limb fracture
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ankle fracture
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Head injury
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laceration
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower limb fracture
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus injury
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Radius fracture
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Road traffic accident
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal fracture
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial bones fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Femoral neck fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Humerus fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incisional hernia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint dislocation
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periprosthetic osteolysis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pubis fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Traumatic intracranial haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention postoperative
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wrist fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Accidental overdose
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Avulsion fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract operation complication
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical vertebral fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clavicle fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Concussion
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Contusion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Craniocerebral injury
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extradural haematoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fibula fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Flatback syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture displacement
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fractured ischium
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fractured sacrum
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ligament rupture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ligament sprain
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Periprosthetic fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural complication
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural haematoma
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative ileus
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative respiratory failure
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural intestinal perforation
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural pain
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Procedural vomiting
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal compression fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sternal fracture
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress fracture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Subdural haemorrhage
Additional description: One treatment-emergent death occurred in participant who also suffered from cerebrovascular accident during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Tendon injury
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon rupture
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ulna fracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound secretion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Congenital, familial and genetic disorders
Congenital cerebrovascular anomaly
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Atrial fibrillation
subjects affected / exposed	5 / 427 (1.17%)	15 / 1507 (1.00%)	16 / 1531 (1.05%)
occurrences causally related to treatment / all	0 / 6	0 / 20	0 / 20
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina pectoris
subjects affected / exposed	3 / 427 (0.70%)	10 / 1507 (0.66%)	6 / 1531 (0.39%)
occurrences causally related to treatment / all	0 / 4	0 / 10	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery disease
subjects affected / exposed	2 / 427 (0.47%)	7 / 1507 (0.46%)	7 / 1531 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 7	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial infarction
Additional description: Four treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
subjects affected / exposed	0 / 427 (0.00%)	13 / 1507 (0.86%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 13	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 4	0 / 0
Cardiac failure congestive
Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
subjects affected / exposed	1 / 427 (0.23%)	8 / 1507 (0.53%)	6 / 1531 (0.39%)
occurrences causally related to treatment / all	1 / 1	1 / 11	1 / 8
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Acute myocardial infarction
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	1 / 427 (0.23%)	5 / 1507 (0.33%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Sinus node dysfunction
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradycardia
subjects affected / exposed	0 / 427 (0.00%)	4 / 1507 (0.27%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve incompetence
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac arrest
Additional description: Two treatment-emergent deaths occurred during treatment with placebo (in high-risk group) and were not related.
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 2	0 / 0
Ventricular tachycardia
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Acute coronary syndrome
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery stenosis
subjects affected / exposed	1 / 427 (0.23%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina unstable
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arrhythmia
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial flutter
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myocardial ischaemia
Additional description: One treatment-emergent death occurred during treatment with pioglitazone (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 1
Aortic valve stenosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrioventricular block complete
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coronary artery occlusion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Supraventricular tachycardia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular fibrillation
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriosclerosis coronary artery
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arteriospasm coronary
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial septal defect acquired
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bradyarrhythmia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac failure chronic
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac tamponade
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Mitral valve disease
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Palpitations
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Stress cardiomyopathy
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tricuspid valve incompetence
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ventricular extrasystoles
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Syncope
subjects affected / exposed	2 / 427 (0.47%)	13 / 1507 (0.86%)	14 / 1531 (0.91%)
occurrences causally related to treatment / all	0 / 2	0 / 13	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient ischaemic attack
subjects affected / exposed	0 / 427 (0.00%)	11 / 1507 (0.73%)	10 / 1531 (0.65%)
occurrences causally related to treatment / all	0 / 0	0 / 11	1 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebrovascular accident
Additional description: One treatment-emergent death occurred in participant who also suffered from subdural haemorrhage during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	1 / 427 (0.23%)	10 / 1507 (0.66%)	6 / 1531 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 10	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Presyncope
subjects affected / exposed	1 / 427 (0.23%)	4 / 1507 (0.27%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 4	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carotid artery stenosis
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ischaemic stroke
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral haemorrhage
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Seizure
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Generalised tonic-clonic seizure
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intracranial aneurysm
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Somnolence
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Transient global amnesia
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Amnesia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Aphasia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Carpal tunnel syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral infarction
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dizziness postural
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Encephalopathy
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial neuralgia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Facial paralysis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhage intracranial
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Haemorrhagic stroke
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
IIIrd nerve paralysis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lacunar infarction
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lacunar stroke
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolic encephalopathy
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nerve compression
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Paraplegia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Parkinson's disease
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sciatica
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal cord compression
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Temporal lobe epilepsy
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Blood and lymphatic system disorders
Anaemia
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemolytic anaemia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhagic anaemia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ear and labyrinth disorders
Vertigo
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertigo positional
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Macular fibrosis
subjects affected / exposed	2 / 427 (0.47%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 2	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cataract
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dacryostenosis acquired
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Macular oedema
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Neovascular age-related macular degeneration
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	1 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Small intestinal obstruction
subjects affected / exposed	0 / 427 (0.00%)	8 / 1507 (0.53%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 8	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Inguinal hernia
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal obstruction
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rectal haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum intestinal haemorrhagic
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus hernia
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Constipation
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diarrhoea
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticular perforation
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diverticulum
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrooesophageal reflux disease
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Irritable bowel syndrome
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Obstructive pancreatitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Umbilical hernia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Upper gastrointestinal haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vomiting
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal adhesions
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abdominal pain lower
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colitis ischaemic
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Duodenal stenosis
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dyspepsia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Functional gastrointestinal disorder
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gallstone ileus
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastric ulcer haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haemorrhoids
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Ileus
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Impaired gastric emptying
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Incarcerated inguinal hernia
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intestinal pseudo-obstruction
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Large intestine polyp
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nausea
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Oesophageal spasm
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pancreatitis acute
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Volvulus
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Angioedema
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Precancerous skin lesion
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Acute kidney injury
subjects affected / exposed	3 / 427 (0.70%)	5 / 1507 (0.33%)	7 / 1531 (0.46%)
occurrences causally related to treatment / all	0 / 3	0 / 5	0 / 7
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary retention
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Haematuria
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nephrolithiasis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract obstruction
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal failure
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary incontinence
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Calculus bladder
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chronic kidney disease
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic nephropathy
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower urinary tract symptoms
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral obstruction
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urethral stenosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinoma
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Thyroid mass
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	4 / 427 (0.94%)	22 / 1507 (1.46%)	23 / 1531 (1.50%)
occurrences causally related to treatment / all	0 / 6	0 / 24	0 / 26
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthralgia
subjects affected / exposed	3 / 427 (0.70%)	13 / 1507 (0.86%)	10 / 1531 (0.65%)
occurrences causally related to treatment / all	0 / 3	0 / 14	0 / 10
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthritis
subjects affected / exposed	1 / 427 (0.23%)	6 / 1507 (0.40%)	8 / 1531 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 6	0 / 11
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Back pain
subjects affected / exposed	2 / 427 (0.47%)	4 / 1507 (0.27%)	5 / 1531 (0.33%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 5
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rotator cuff syndrome
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc degeneration
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal chest pain
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal pain
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal column stenosis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lumbar spinal stenosis
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscular weakness
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Arthropathy
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bursitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cervical spinal stenosis
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intervertebral disc protrusion
subjects affected / exposed	1 / 427 (0.23%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in extremity
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Dupuytren's contracture
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Foot deformity
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fracture pain
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint instability
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Joint range of motion decreased
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Muscle haemorrhage
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal discomfort
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Myosclerosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteonecrosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pain in jaw
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Polymyalgia rheumatica
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sacroiliitis
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Scoliosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Seronegative arthritis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spinal osteoarthritis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Spondylolisthesis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Synovial cyst
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tendon disorder
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebral foraminal stenosis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vertebral osteophyte
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
Additional description: One treatment-emergent death occurred during treatment with placebo (in high-risk group) and was not related.
subjects affected / exposed	3 / 427 (0.70%)	12 / 1507 (0.80%)	15 / 1531 (0.98%)
occurrences causally related to treatment / all	0 / 3	0 / 13	0 / 15
deaths causally related to treatment / all	0 / 0	0 / 1	0 / 0
Diverticulitis
subjects affected / exposed	3 / 427 (0.70%)	7 / 1507 (0.46%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 3	0 / 7	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cellulitis
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	8 / 1531 (0.52%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 9
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sepsis
subjects affected / exposed	1 / 427 (0.23%)	5 / 1507 (0.33%)	6 / 1531 (0.39%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 6
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urosepsis
subjects affected / exposed	2 / 427 (0.47%)	4 / 1507 (0.27%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 4	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Urinary tract infection
subjects affected / exposed	1 / 427 (0.23%)	5 / 1507 (0.33%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 5	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Appendicitis
subjects affected / exposed	2 / 427 (0.47%)	1 / 1507 (0.07%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 2	0 / 1	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis
subjects affected / exposed	0 / 427 (0.00%)	3 / 1507 (0.20%)	4 / 1531 (0.26%)
occurrences causally related to treatment / all	0 / 0	0 / 3	0 / 4
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower respiratory tract infection
subjects affected / exposed	1 / 427 (0.23%)	2 / 1507 (0.13%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Influenza
subjects affected / exposed	0 / 427 (0.00%)	4 / 1507 (0.27%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 4	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile colitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	2 / 1531 (0.13%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pyelonephritis
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Wound infection
subjects affected / exposed	1 / 427 (0.23%)	2 / 1507 (0.13%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Abscess limb
subjects affected / exposed	1 / 427 (0.23%)	0 / 1507 (0.00%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Anal abscess
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchiolitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Bronchitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 2
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Clostridium difficile infection
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Coccidioidomycosis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Colonic abscess
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Device related infection
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia sepsis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Escherichia urinary tract infection
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infected skin ulcer
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infective exacerbation of bronchiectasis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Klebsiella sepsis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Labyrinthitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Localised infection
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meningoencephalitis herpetic
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Osteomyelitis
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumocystis jirovecii pneumonia
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia bacterial
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia klebsiella
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Post procedural cellulitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative wound infection
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory syncytial virus bronchitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory tract infection
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Septic shock
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Sinusitis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Staphylococcal sepsis
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Dehydration
subjects affected / exposed	1 / 427 (0.23%)	3 / 1507 (0.20%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 1	0 / 3	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hyponatraemia
subjects affected / exposed	0 / 427 (0.00%)	2 / 1507 (0.13%)	3 / 1531 (0.20%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cerebral salt-wasting syndrome
subjects affected / exposed	0 / 427 (0.00%)	0 / 1507 (0.00%)	1 / 1531 (0.07%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hypokalaemia
subjects affected / exposed	0 / 427 (0.00%)	1 / 1507 (0.07%)	0 / 1531 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Low Risk Placebo	High Risk Placebo	High Risk Pioglitazone
Total subjects affected by non serious adverse events
subjects affected / exposed	235 / 427 (55.04%)	828 / 1507 (54.94%)	822 / 1531 (53.69%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma
subjects affected / exposed	23 / 427 (5.39%)	59 / 1507 (3.92%)	71 / 1531 (4.64%)
occurrences all number	27	74	89
Injury, poisoning and procedural complications
Fall
subjects affected / exposed	18 / 427 (4.22%)	143 / 1507 (9.49%)	135 / 1531 (8.82%)
occurrences all number	24	171	176
Vascular disorders
Hypertension
subjects affected / exposed	26 / 427 (6.09%)	97 / 1507 (6.44%)	93 / 1531 (6.07%)
occurrences all number	26	100	94
Eye disorders
Cataract
subjects affected / exposed	27 / 427 (6.32%)	119 / 1507 (7.90%)	106 / 1531 (6.92%)
occurrences all number	33	159	149
Gastrointestinal disorders
Constipation
subjects affected / exposed	24 / 427 (5.62%)	70 / 1507 (4.64%)	72 / 1531 (4.70%)
occurrences all number	24	75	75
Respiratory, thoracic and mediastinal disorders
Cough
subjects affected / exposed	20 / 427 (4.68%)	79 / 1507 (5.24%)	76 / 1531 (4.96%)
occurrences all number	23	88	87
Musculoskeletal and connective tissue disorders
Arthralgia
subjects affected / exposed	45 / 427 (10.54%)	125 / 1507 (8.29%)	125 / 1531 (8.16%)
occurrences all number	54	145	148
Back pain
subjects affected / exposed	31 / 427 (7.26%)	82 / 1507 (5.44%)	101 / 1531 (6.60%)
occurrences all number	32	89	109
Osteoarthritis
subjects affected / exposed	19 / 427 (4.45%)	81 / 1507 (5.37%)	86 / 1531 (5.62%)
occurrences all number	22	90	95
Infections and infestations
Upper respiratory tract infection
subjects affected / exposed	62 / 427 (14.52%)	190 / 1507 (12.61%)	183 / 1531 (11.95%)
occurrences all number	85	255	239
Urinary tract infection
subjects affected / exposed	47 / 427 (11.01%)	178 / 1507 (11.81%)	191 / 1531 (12.48%)
occurrences all number	78	305	302
Nasopharyngitis
subjects affected / exposed	22 / 427 (5.15%)	72 / 1507 (4.78%)	90 / 1531 (5.88%)
occurrences all number	24	88	106
Sinusitis
subjects affected / exposed	22 / 427 (5.15%)	67 / 1507 (4.45%)	52 / 1531 (3.40%)
occurrences all number	27	83	62

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Were there any global substantial amendments to the protocol? Yes

09 Apr 2013

The following changes were made as per Amendment 1: Modified the order of the cognitive test battery. Changed the Informed Consent for Project Partner to a Project Partner Acknowledgement Form. Modified the randomization in an amyloid-related imaging abnormalities (ARIA) substudy.

19 Mar 2014

The following changes were made as per Amendment 2: Changed the timing of the ad hoc magnetic resonance imaging (MRI) done in conjunction with MCI due to AD diagnosis from the first of the 2 consecutive visits to the end of the second Comprehensive Medical Follow-Up Visit. Deleted an inclusion criterion regarding the requirement for vitamin D and calcium. Corrected the description of mandatory risk stratification genetic sample processing. Changed the ARIA substudy to a substudy focused on volumetric MRI changes, and removed ARIA from the list of adverse events of special interest (AESIs).

10 Nov 2014

The following changes were made as per Amendment 3: Provided sites with an option to consent subjects with a full study informed consent at Visit 1 or a split Screening informed consent at Visit 1 (Screening) and a Study entry informed consent at Visit 2 (Baseline). Extended the visit window for screening to randomization, to provide additional flexibility in scheduling Baseline and Randomization Visits if needed, once risk stratification sample results were obtained from Screening Visit and cognitive battery test results were obtained from Baseline Visit. Provided the option for sites to include subject consent to pharmacogenomics (PGx) research within the main study informed consent form. Replaced the health care resource utilization (HCRU) instrument with the Alzheimer’s Disease Cooperative Study—Resource Use Inventory (ADCS-RUI) and updated the schedule of this assessment. Permitted sites to perform the screening visit at a subject’s home, after review and approval by the sponsor of the site’s procedures, to provide additional flexibility for scheduling and subject comfort. Permitted sites to administer the Clinical Dementia Rating (CDR) assessment prior to the cognitive battery only during the Baseline Visit, and to administer the Alzheimer’s Disease Cooperative Study—Clinical Global Impression of Change—Mild Cognitive Impairment (ADCS-CGIC-MCI) in parallel with the other cognitive assessments. Reduced the Short Form-36 (SF-36) and European Quality of Life (EQ-5D) assessment schedule.

24 Jul 2015

The following changes were made as per Amendment 5: Revised treatment effect size assumption. Removed Russia and Italy as countries for site participation. Corrected exclusion criteria numbers 9 and14. Updated excluded medications table to clarify the exclusion of treatment for Parkinson disease. Updated the assessor expectations for the ADCS-RUI assessment.

27 Sep 2016

The following changes were made as per Amendment 6: Revised the efficacy futility analysis to occur once 33% of events had accrued, rather than at 50%. Added an operational futility analysis to enable an assessment of whether the study could feasibly be completed within an acceptable timeframe, based on the accrual rate of adjudicated cases meeting the event definition. Clarified the timing of required MRI scans and removed the requirement to perform an MRI scan if a scan was performed for the study within the preceding 6 months. Introduced additional options for the performance of the Comprehensive Medical Follow-Up Visit, including the ability to perform assessments during routine Month 6 or Month 12 visits in certain situations and during home visits or by telephone (for project partners) in exceptional circumstances. Made microscopic urine screens standard on all urine sample collections at routine visits rather than as a reflex in the event of abnormalities detected on macroscopic examination. Introduced formal limits for assessment of compliance with study drug to help facilitate consistency in global monitoring and reporting of subjects that were not compliant with administration of study drug. Clarified AESI follow-up and reporting of macular degeneration and hypoglycemia to ensure consistency in follow-up of macular edema and to eliminate ambiguity over reporting of hypoglycemia as an AESI, ensuring consistency across all subjects.

Were there any global interruptions to the trial? Yes

Date	Interruption	Restart date
07 Aug 2018	Terminated due to lack of efficacy of the drug and had no safety concern.	-

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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