TOMMORROW: Biomarker Qualification for Risk of Mild Cognitive Impairment (MCI) Due to Alzheimer's Disease (AD) and Safety and Efficacy Evaluation of Pioglitazone in Delaying Its Onset
Sponsor
Takeda (Industry)
Overall Status
Terminated
CT.gov ID
NCT01931566
Collaborator
Zinfandel Pharmaceuticals Inc. (Industry)
3,494
55
3
61.2
63.5
1
Study Details
Study Description
Brief Summary
The purpose of this study is to qualify the biomarker risk algorithm for prognosis of the risk of developing Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD), and also to evaluate the efficacy of pioglitazone compared with placebo to delay the onset of MCI-AD in cognitively-normal participants who are at high-risk for developing MCI within 5 years.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
Detailed Description
This study has two goals. One of these goals is to see if a new genetic test can determine if participants are at risk of developing Mild Cognitive Impairment due to Alzheimer's Disease (MCI-AD) within the next five years. The other goal is to evaluate the study drug called pioglitazone. Pioglitazone is being tested to delay the onset of MCI-AD. This study will look at the effectiveness of pioglitazone in delaying the onset of MCI-AD in cognitively-normal people who are at high-risk of developing MCI-AD, as identified by the biomarker in the non-Hispanic/Latino Caucasian participants.
This multi-centre trial will be conducted worldwide. The study will enroll approximately 3500 subjects. Participants will be assigned to high or low risk groups for developing MCI- AD within the next five years, based on the results of the biomarker risk algorithm. Participants in the high risk group will be randomly assigned to one of the two treatment groups-which will remain unknown to the participant and study doctor during the study (unless there is an urgent medical need):
-
Pioglitazone tablet
-
Placebo (dummy inactive pill) - this is a tablet that looks like the study drug but has no active ingredient.
Participants in the low risk group will be assigned to placebo. The assignment of each participant to the high or low risk group, as well as the participant's treatment assignment, will remain undisclosed to the participants and study doctor during the study (unless there is an urgent medical need).
All participants will be asked to take one tablet at the same time each day throughout the study.
The overall time to participate in this study is approximately 5 years. Participants will make up to 14 visits to the clinic, and will be contacted by telephone 3 months after each treatment visit for a follow-up assessment, and 2 weeks after the final visit.
Study Design
Study Type:
Interventional
Actual Enrollment
:
3494 participants
Allocation:
Randomized
Intervention Model:
Parallel Assignment
Masking:
Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose:
Treatment
Official Title:
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
Actual Study Start Date
:
Aug 1, 2013
Actual Primary Completion Date
:
Jul 24, 2018
Actual Study Completion Date
:
Sep 6, 2018
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Placebo Comparator: Low Risk Placebo Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to low risk group for developing MCI-AD for up to 5 years. |
Drug: Pioglitazone placebo
Pioglitazone placebo-matching tablets
|
| Placebo Comparator: High Risk Placebo Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. |
Drug: Pioglitazone placebo
Pioglitazone placebo-matching tablets
|
| Experimental: High Risk Pioglitazone 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. |
Drug: Pioglitazone
Pioglitazone SR tablets
|
Outcome Measures
Primary Outcome Measures
- 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 [Baseline to the end of study (approximately up to 5 years)]
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.
- 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 [Baseline to the end of study (approximately up to 5 years)]
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.
Secondary Outcome Measures
- 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 [Baseline and Month 48]
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 baseline, a higher composite score indicated better cognition.
- 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 [Baseline and Month 48]
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.
Eligibility Criteria
Criteria
Ages Eligible for Study:
65 Years
to 83 Years
Sexes Eligible for Study:
All
Accepts Healthy Volunteers:
Yes
Inclusion Criteria:
-
In the opinion of the investigator, participant is capable of understanding and complying with protocol requirements.
-
Signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedures.
-
Is able to physically perform the cognitive tests in the opinion of the investigator and is fluent in the language that tests will be administered.
-
Is cognitively normal at baseline, scoring as indicated for the following tests:
-
Clinical Dementia Rating (CDR)=0.
-
At least one memory test above -1.5 standard deviation (SD) of the demographically corrected normative mean.
-
Must score ≥25 on the Mini-Mental State Examination (MMSE) at the screening visit after the education and age adjustment.
-
Is male or postmenopausal female between the ages of 65 and 83 years, inclusive, at time of the Screening visit.
-
Has the ability and intention to participate in regular study visits, in the opinion of the Investigator.
-
Has a project partner who can separately complete an Acknowledgement Form on his/her own behalf and take part in the study (with the intent to do so as long as the participant is enrolled) to provide information on the cognitive, functional, and behavioral status of the participant and to assist with monitoring of study medication, if needed.
Exclusion Criteria:
-
Has a current diagnosis or history of any type of cognitive impairment or dementia or has a current diagnosis or history of neurological/psychiatric disorder or any other diagnosis that significantly affects cognitive performance (eg, mental retardation, organic mental disorder).
-
Has a current diagnosis of significant psychiatric illness, per Diagnostic & Statistical Manual of Mental Disorders, 4th Edition - Text Revision (DSM-IV-TR) (or DSM-V when published) (including but not limited to major depressive disorder, anxiety disorders) and is in an acute phase/episode, or the participant has a current diagnosis or history of schizophrenia or bipolar disorder.
-
Has a glycosylated hemoglobin (HbA1c) >8.0% at the time of baseline or requires treatment with insulin, triple oral antidiabetic therapy or a peroxisome proliferator-activated receptor-gamma (PPAR-γ) agonist. The participant should be on a stable antidiabetic regimen for at least 3 months prior to enrollment.
-
Has a clinically significant unstable illness, for example, hepatic impairment or renal insufficiency, or cardiovascular, pulmonary, gastrointestinal (including s/p gastric bypass), endocrine, neurological, rheumatologic, immunologic, infectious, skin and subcutaneous tissue disorders, or metabolic disturbance. History of HIV infection is considered exclusionary for this study.
-
Has a history of drug abuse (defined as any illicit drug use) or a history of alcohol abuse/dependence within 2 years prior to the Screening Visit.
-
Is an immediate family member, testing center employee, or is in a dependent relationship with a testing center employee who is involved in conduct of this study (eg, spouse, parent, child, and sibling) or may consent under duress.
-
Has a history of hypersensitivity or allergies to pioglitazone or related compounds.
-
Is required to take excluded medications as specified in the Excluded Medications Section.
-
Had any of the following values at the Baseline Visit (Visit 2):
-
A serum total bilirubin value >1.5× upper limit of normal (ULN).
-
A serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) value
2xULN.
-
Unexplained microscopic/macroscopic hematuria on one repeat examinations within 2 weeks of the initial assessment.
-
Is positive for either Hepatitis B surface antigen (HBsAg) or anti-hepatitis C virus (HCV) antibodies at the Baseline Visit (Visit 2).
-
Has a condition or takes medication that, in the opinion of the Investigator, could interfere with the assessments of safety, tolerability, or efficacy, or prevent the participant from adequately participating in the study or continue for the anticipated duration of the study.
-
Has received any investigational compound within 30 days prior to screening or 5 half-lives prior to Screening or is currently participating in another study which entails the administration of an investigational or marketed drug, supplement or intervention including, but not limited to diet, exercise, lifestyle or invasive procedure.
-
Has a history of any cancer that has been in remission for less than 2 years from the Screening Visit. Participants with basal cell or stage I squamous cell carcinoma of the skin will be eligible. Participants with history of bladder cancer are not eligible irrespective of the remission status.
-
Has a history or current diagnosis of macular edema or macular degeneration.
-
If female, has a history of postmenopausal fractures with no or minimal trauma (eg, wrist, hip, lumbar or thoracic vertebral fracture).
-
Has a history or current diagnosis of congestive heart failure (CHF), New York Heart Association Class III-IV.
-
Has been exposed to the cognitive tests performed in this study within 6 months prior to the Screening Visit, with the exception of the MMSE.
-
Participant's Translocase of the Outer Mitochondrial Membrane 40 homolog (TOMM40) rs10524523 or apolipoprotein E (APOE) genotypes or APOE phenotype are known by the participant or the study staff participating in this study.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Phoenix | Arizona | United States | ||
| 2 | Sun City | Arizona | United States | ||
| 3 | Long Beach | California | United States | ||
| 4 | San Diego | California | United States | ||
| 5 | San Francisco | California | United States | ||
| 6 | Delray Beach | Florida | United States | ||
| 7 | Fort Myers | Florida | United States | ||
| 8 | Lady Lake | Florida | United States | ||
| 9 | Lake Worth | Florida | United States | ||
| 10 | Merritt Island | Florida | United States | ||
| 11 | Orlando | Florida | United States | ||
| 12 | Port Orange | Florida | United States | ||
| 13 | Saint Petersburg | Florida | United States | ||
| 14 | Weston | Florida | United States | ||
| 15 | Atlanta | Georgia | United States | ||
| 16 | Decatur | Georgia | United States | ||
| 17 | Chicago | Illinois | United States | ||
| 18 | Elk Grove Village | Illinois | United States | ||
| 19 | Elk Grove | Illinois | United States | ||
| 20 | Iowa City | Iowa | United States | ||
| 21 | Farmington Hills | Michigan | United States | ||
| 22 | Saint Louis | Missouri | United States | ||
| 23 | Las Vegas | Nevada | United States | ||
| 24 | Marlton | New Jersey | United States | ||
| 25 | New York | New York | United States | ||
| 26 | Concord | North Carolina | United States | ||
| 27 | Durham | North Carolina | United States | ||
| 28 | Akron | Ohio | United States | ||
| 29 | Portland | Oregon | United States | ||
| 30 | Charleston | South Carolina | United States | ||
| 31 | Cordova | Tennessee | United States | ||
| 32 | Houston | Texas | United States | ||
| 33 | Salt Lake City | Utah | United States | ||
| 34 | Middleton | Wisconsin | United States | ||
| 35 | North Ryde | New South Wales | Australia | ||
| 36 | Southport | Queensland | Australia | ||
| 37 | West Heidelberg | Victoria | Australia | ||
| 38 | Nedlands | Western Australia | Australia | ||
| 39 | Stuttgart | Baden Wuerttemberg | Germany | ||
| 40 | Siegen | Nordrhein Westfalen | Germany | ||
| 41 | Halle | Sachsen Anhalt | Germany | ||
| 42 | Berlin | Germany | |||
| 43 | Basel | Switzerland | |||
| 44 | Exeter | Devon | United Kingdom | ||
| 45 | Plymouth | Devon | United Kingdom | ||
| 46 | Hammersmith | Greater London | United Kingdom | ||
| 47 | London | Greater London | United Kingdom | ||
| 48 | Manchester | Greater Manchester | United Kingdom | ||
| 49 | Salford | Greater Manchester | United Kingdom | ||
| 50 | Blackpool | Lancashire | United Kingdom | ||
| 51 | Isleworth | Middlesex | United Kingdom | ||
| 52 | Glasgow | Strathclyde | United Kingdom | ||
| 53 | Dundee | Tayside Region | United Kingdom | ||
| 54 | Perth | Tayside Region | United Kingdom | ||
| 55 | Bristol | United Kingdom |
Sponsors and Collaborators
- Takeda
- Zinfandel Pharmaceuticals Inc.
Investigators
- Study Director: Medical Director, Takeda
Study Documents (Full-Text)
More Information
Publications
None provided.Responsible Party:
Takeda
ClinicalTrials.gov Identifier:
NCT01931566
Other Study ID Numbers:
- AD-4833/TOMM40_301
- 2012-003111-58
- U1111-1139-0355
First Posted:
Aug 29, 2013
Last Update Posted:
Sep 16, 2019
Last Verified:
Aug 1, 2019
Individual Participant Data (IPD) Sharing Statement:
Yes
Plan to Share IPD:
Yes
Keywords provided by Takeda
Additional relevant MeSH terms:
Study Results
Participant Flow
| 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. |
|---|---|
| Pre-assignment Detail | Participants at least 65 years old with normal cognitive function were enrolled to receive either pioglitazone (0.8 mg sustained release tablet) or placebo. |
| Arm/Group Title | Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone |
|---|---|---|---|
| Arm/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. | Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. | 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. |
| Period Title: Overall Study | |||
| STARTED | 433 | 1516 | 1545 |
| Treated | 427 | 1507 | 1531 |
| COMPLETED | 4 | 40 | 39 |
| NOT COMPLETED | 429 | 1476 | 1506 |
Baseline Characteristics
| Arm/Group Title | Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone | Total |
|---|---|---|---|---|
| Arm/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. | Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. | 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. | Total of all reporting groups |
| Overall Participants | 433 | 1516 | 1545 | 3494 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
70.3
(4.02)
|
74.6
(5.27)
|
74.4
(5.25)
|
74.0
(5.31)
|
| Age, Customized (Count of Participants) | ||||
| <75 years |
360
83.1%
|
632
41.7%
|
658
42.6%
|
1650
47.2%
|
| >=75 years |
73
16.9%
|
884
58.3%
|
887
57.4%
|
1844
52.8%
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
259
59.8%
|
850
56.1%
|
812
52.6%
|
1921
55%
|
| Male |
174
40.2%
|
666
43.9%
|
733
47.4%
|
1573
45%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
8
1.8%
|
19
1.3%
|
12
0.8%
|
39
1.1%
|
| Not Hispanic or Latino |
425
98.2%
|
1497
98.7%
|
1533
99.2%
|
3455
98.9%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
4
0.3%
|
4
0.1%
|
| Asian |
1
0.2%
|
10
0.7%
|
14
0.9%
|
25
0.7%
|
| Black or African American |
10
2.3%
|
38
2.5%
|
39
2.5%
|
87
2.5%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
1
0.1%
|
1
0.1%
|
2
0.1%
|
| White |
421
97.2%
|
1463
96.5%
|
1484
96.1%
|
3368
96.4%
|
| Multiracial |
1
0.2%
|
4
0.3%
|
3
0.2%
|
8
0.2%
|
| Race/Ethnicity, Customized (Count of Participants) | ||||
| Non-Hispanic/Latino Caucasian |
413
95.4%
|
1444
95.3%
|
1472
95.3%
|
3329
95.3%
|
| Hispanic/Latino and/or non-Caucasian |
20
4.6%
|
72
4.7%
|
73
4.7%
|
165
4.7%
|
| Region of Enrollment (Count of Participants) | ||||
| United States |
270
62.4%
|
962
63.5%
|
985
63.8%
|
2217
63.5%
|
| United Kingdom |
102
23.6%
|
311
20.5%
|
315
20.4%
|
728
20.8%
|
| Australia |
56
12.9%
|
215
14.2%
|
218
14.1%
|
489
14%
|
| Switzerland |
3
0.7%
|
18
1.2%
|
18
1.2%
|
39
1.1%
|
| Germany |
2
0.5%
|
10
0.7%
|
9
0.6%
|
21
0.6%
|
Outcome Measures
| 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 |
|---|---|
| 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. |
| Time Frame | Baseline to the end of study (approximately up to 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | Low Risk Placebo | High Risk Placebo |
|---|---|---|
| Arm/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. | Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. |
| Measure Participants | 402 | 1406 |
| Mean (Full Range) [days] |
905.44
|
1238.67
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low Risk Placebo, High Risk Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Other | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.023 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | ||
| 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 |
|---|---|
| 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. |
| Time Frame | Baseline to the end of study (approximately up to 5 years) |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. |
| Arm/Group Title | High Risk Placebo | High Risk Pioglitazone |
|---|---|---|
| Arm/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. | 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. |
| Measure Participants | 1406 | 1430 |
| Mean (Full Range) [days] |
1238.67
|
1261.24
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Low Risk Placebo, High Risk Placebo |
|---|---|---|
| Comments | ||
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.307 |
| Comments | ||
| Method | Regression, Cox | |
| Comments | ||
| 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 |
|---|---|
| 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 baseline, a higher composite score indicated better cognition. |
| Time Frame | Baseline and Month 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. Number analyzed is the number of participants with evaluable data at the given time-point. |
| Arm/Group Title | High Risk Placebo | High Risk Pioglitazone |
|---|---|---|
| Arm/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. | 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. |
| Measure Participants | 1406 | 1430 |
| Mean (Standard Deviation) [score on a scale] |
0.1841
(0.27508)
|
0.1687
(0.40621)
|
| 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 |
|---|---|
| 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. |
| Time Frame | Baseline and Month 48 |
Outcome Measure Data
| Analysis Population Description |
|---|
| 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. Number analyzed is the number of participants with evaluable data at the given time-point. |
| Arm/Group Title | High Risk Placebo | High Risk Pioglitazone |
|---|---|---|
| Arm/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. | 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. |
| Measure Participants | 1406 | 1430 |
| Mean (Standard Deviation) [score on a scale] |
0.1
(4.93)
|
0.3
(5.32)
|
Adverse Events
| Time Frame | Baseline up to 30 days after the last dose of study drug (up to 935 days) | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting 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. | |||||
| Arm/Group Title | Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone | |||
| Arm/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. | Pioglitazone placebo-matching tablets, orally, once daily to participants assigned to high risk group for developing MCI-AD for up to 5 years. | 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. | |||
All Cause Mortality |
||||||
| Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 2/427 (0.5%) | 21/1507 (1.4%) | 7/1531 (0.5%) | |||
Serious Adverse Events |
||||||
| Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 81/427 (19%) | 404/1507 (26.8%) | 358/1531 (23.4%) | |||
| Blood and lymphatic system disorders | ||||||
| Anaemia | 0/427 (0%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Haemolytic anaemia | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Haemorrhagic anaemia | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cardiac disorders | ||||||
| Atrial fibrillation | 5/427 (1.2%) | 15/1507 (1%) | 16/1531 (1%) | |||
| Angina pectoris | 3/427 (0.7%) | 10/1507 (0.7%) | 6/1531 (0.4%) | |||
| Coronary artery disease | 2/427 (0.5%) | 7/1507 (0.5%) | 7/1531 (0.5%) | |||
| Myocardial infarction | 0/427 (0%) | 13/1507 (0.9%) | 3/1531 (0.2%) | |||
| Cardiac failure congestive | 1/427 (0.2%) | 8/1507 (0.5%) | 6/1531 (0.4%) | |||
| Acute myocardial infarction | 1/427 (0.2%) | 5/1507 (0.3%) | 3/1531 (0.2%) | |||
| Sinus node dysfunction | 0/427 (0%) | 2/1507 (0.1%) | 5/1531 (0.3%) | |||
| Bradycardia | 0/427 (0%) | 4/1507 (0.3%) | 2/1531 (0.1%) | |||
| Mitral valve incompetence | 0/427 (0%) | 1/1507 (0.1%) | 5/1531 (0.3%) | |||
| Cardiac arrest | 0/427 (0%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Ventricular tachycardia | 1/427 (0.2%) | 3/1507 (0.2%) | 1/1531 (0.1%) | |||
| Acute coronary syndrome | 1/427 (0.2%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Coronary artery stenosis | 1/427 (0.2%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Angina unstable | 0/427 (0%) | 3/1507 (0.2%) | 0/1531 (0%) | |||
| Arrhythmia | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Atrial flutter | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Myocardial ischaemia | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Aortic valve stenosis | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Atrioventricular block complete | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Coronary artery occlusion | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Extrasystoles | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Supraventricular tachycardia | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Ventricular fibrillation | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Arteriosclerosis coronary artery | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Arteriospasm coronary | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Atrial septal defect acquired | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Bradyarrhythmia | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cardiac failure chronic | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cardiac tamponade | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Mitral valve disease | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Palpitations | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Stress cardiomyopathy | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Tricuspid valve incompetence | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Ventricular extrasystoles | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Congenital, familial and genetic disorders | ||||||
| Congenital cerebrovascular anomaly | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Ear and labyrinth disorders | ||||||
| Vertigo | 1/427 (0.2%) | 1/1507 (0.1%) | 3/1531 (0.2%) | |||
| Vertigo positional | 1/427 (0.2%) | 3/1507 (0.2%) | 0/1531 (0%) | |||
| Endocrine disorders | ||||||
| Thyroid mass | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Eye disorders | ||||||
| Macular fibrosis | 2/427 (0.5%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Cataract | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Dacryostenosis acquired | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Macular oedema | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Neovascular age-related macular degeneration | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Gastrointestinal disorders | ||||||
| Small intestinal obstruction | 0/427 (0%) | 8/1507 (0.5%) | 5/1531 (0.3%) | |||
| Abdominal pain | 0/427 (0%) | 2/1507 (0.1%) | 5/1531 (0.3%) | |||
| Inguinal hernia | 0/427 (0%) | 2/1507 (0.1%) | 4/1531 (0.3%) | |||
| Intestinal obstruction | 0/427 (0%) | 3/1507 (0.2%) | 3/1531 (0.2%) | |||
| Rectal haemorrhage | 0/427 (0%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Colitis | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Diverticulum intestinal haemorrhagic | 1/427 (0.2%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Gastrointestinal haemorrhage | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Hiatus hernia | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Pancreatitis | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Constipation | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Diarrhoea | 1/427 (0.2%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Diverticular perforation | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Diverticulum | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Gastrooesophageal reflux disease | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Irritable bowel syndrome | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Obstructive pancreatitis | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Umbilical hernia | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Upper gastrointestinal haemorrhage | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Vomiting | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Abdominal adhesions | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Abdominal pain lower | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Colitis ischaemic | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Duodenal stenosis | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Dyspepsia | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Functional gastrointestinal disorder | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Gallstone ileus | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Gastric ulcer haemorrhage | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Haemorrhoids | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Ileus | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Impaired gastric emptying | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Incarcerated inguinal hernia | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Intestinal pseudo-obstruction | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Large intestine polyp | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Nausea | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Oesophageal spasm | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pancreatitis acute | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Volvulus | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| General disorders | ||||||
| Non-cardiac chest pain | 0/427 (0%) | 5/1507 (0.3%) | 8/1531 (0.5%) | |||
| Asthenia | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Chest pain | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Hernia | 1/427 (0.2%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pyrexia | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Adverse drug reaction | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Death | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Fatigue | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Ill-defined disorder | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Systemic inflammatory response syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Unevaluable event | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Hepatobiliary disorders | ||||||
| Cholecystitis | 1/427 (0.2%) | 3/1507 (0.2%) | 6/1531 (0.4%) | |||
| Cholecystitis acute | 0/427 (0%) | 3/1507 (0.2%) | 3/1531 (0.2%) | |||
| Cholelithiasis | 2/427 (0.5%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Bile duct stone | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Cholangitis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Cholecystitis chronic | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Drug-induced liver injury | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Jaundice | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Primary biliary cholangitis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Immune system disorders | ||||||
| Anaphylactic reaction | 1/427 (0.2%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Drug hypersensitivity | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Sarcoidosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Infections and infestations | ||||||
| Pneumonia | 3/427 (0.7%) | 12/1507 (0.8%) | 15/1531 (1%) | |||
| Diverticulitis | 3/427 (0.7%) | 7/1507 (0.5%) | 4/1531 (0.3%) | |||
| Cellulitis | 1/427 (0.2%) | 3/1507 (0.2%) | 8/1531 (0.5%) | |||
| Sepsis | 1/427 (0.2%) | 5/1507 (0.3%) | 6/1531 (0.4%) | |||
| Urosepsis | 2/427 (0.5%) | 4/1507 (0.3%) | 4/1531 (0.3%) | |||
| Urinary tract infection | 1/427 (0.2%) | 5/1507 (0.3%) | 3/1531 (0.2%) | |||
| Appendicitis | 2/427 (0.5%) | 1/1507 (0.1%) | 4/1531 (0.3%) | |||
| Gastroenteritis | 0/427 (0%) | 3/1507 (0.2%) | 4/1531 (0.3%) | |||
| Lower respiratory tract infection | 1/427 (0.2%) | 2/1507 (0.1%) | 3/1531 (0.2%) | |||
| Influenza | 0/427 (0%) | 4/1507 (0.3%) | 0/1531 (0%) | |||
| Clostridium difficile colitis | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Pyelonephritis | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Wound infection | 1/427 (0.2%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Abscess limb | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Anal abscess | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Bronchiolitis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Bronchitis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Clostridium difficile infection | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Coccidioidomycosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Colonic abscess | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Device related infection | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Escherichia sepsis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Escherichia urinary tract infection | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Gastroenteritis viral | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Infected skin ulcer | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Infective exacerbation of bronchiectasis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Klebsiella sepsis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Labyrinthitis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Localised infection | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Meningoencephalitis herpetic | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Osteomyelitis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Pneumocystis jirovecii pneumonia | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pneumonia bacterial | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pneumonia klebsiella | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Post procedural cellulitis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Postoperative wound infection | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Respiratory syncytial virus bronchitis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Respiratory tract infection | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Septic shock | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Sinusitis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Staphylococcal sepsis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Injury, poisoning and procedural complications | ||||||
| Fall | 1/427 (0.2%) | 7/1507 (0.5%) | 3/1531 (0.2%) | |||
| Hip fracture | 2/427 (0.5%) | 7/1507 (0.5%) | 2/1531 (0.1%) | |||
| Rib fracture | 0/427 (0%) | 4/1507 (0.3%) | 3/1531 (0.2%) | |||
| Femur fracture | 0/427 (0%) | 3/1507 (0.2%) | 3/1531 (0.2%) | |||
| Subarachnoid haemorrhage | 0/427 (0%) | 4/1507 (0.3%) | 1/1531 (0.1%) | |||
| Upper limb fracture | 1/427 (0.2%) | 3/1507 (0.2%) | 1/1531 (0.1%) | |||
| Ankle fracture | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Head injury | 0/427 (0%) | 3/1507 (0.2%) | 0/1531 (0%) | |||
| Laceration | 1/427 (0.2%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Lower limb fracture | 1/427 (0.2%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Meniscus injury | 0/427 (0%) | 0/1507 (0%) | 3/1531 (0.2%) | |||
| Radius fracture | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Road traffic accident | 0/427 (0%) | 0/1507 (0%) | 3/1531 (0.2%) | |||
| Spinal fracture | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Facial bones fracture | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Femoral neck fracture | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Humerus fracture | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Incisional hernia | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Joint dislocation | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Pelvic fracture | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Periprosthetic osteolysis | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Post procedural haemorrhage | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Pubis fracture | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Traumatic intracranial haemorrhage | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Urinary retention postoperative | 1/427 (0.2%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Wrist fracture | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Accidental overdose | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Avulsion fracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cataract operation complication | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cervical vertebral fracture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Clavicle fracture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Concussion | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Contusion | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Craniocerebral injury | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Extradural haematoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Fibula fracture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Flatback syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Foot fracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Fracture displacement | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Fractured ischium | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Fractured sacrum | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Hand fracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Ligament rupture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Ligament sprain | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Periprosthetic fracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Post procedural complication | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Post procedural haematoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Postoperative ileus | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Postoperative respiratory failure | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Procedural intestinal perforation | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Procedural pain | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Procedural vomiting | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Spinal compression fracture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Sternal fracture | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Stress fracture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Subdural haemorrhage | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Tendon injury | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Tendon rupture | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Ulna fracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Wound secretion | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Investigations | ||||||
| Blood magnesium decreased | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Blood pressure increased | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Electrocardiogram QT prolonged | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Blood parathyroid hormone increased | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Heart rate irregular | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Hepatic enzyme increased | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Platelet count decreased | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Metabolism and nutrition disorders | ||||||
| Dehydration | 1/427 (0.2%) | 3/1507 (0.2%) | 3/1531 (0.2%) | |||
| Hyponatraemia | 0/427 (0%) | 2/1507 (0.1%) | 3/1531 (0.2%) | |||
| Cerebral salt-wasting syndrome | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Hypokalaemia | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Osteoarthritis | 4/427 (0.9%) | 22/1507 (1.5%) | 23/1531 (1.5%) | |||
| Arthralgia | 3/427 (0.7%) | 13/1507 (0.9%) | 10/1531 (0.7%) | |||
| Arthritis | 1/427 (0.2%) | 6/1507 (0.4%) | 8/1531 (0.5%) | |||
| Back pain | 2/427 (0.5%) | 4/1507 (0.3%) | 5/1531 (0.3%) | |||
| Rotator cuff syndrome | 0/427 (0%) | 2/1507 (0.1%) | 4/1531 (0.3%) | |||
| Intervertebral disc degeneration | 0/427 (0%) | 2/1507 (0.1%) | 3/1531 (0.2%) | |||
| Musculoskeletal chest pain | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Musculoskeletal pain | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Spinal column stenosis | 0/427 (0%) | 1/1507 (0.1%) | 3/1531 (0.2%) | |||
| Lumbar spinal stenosis | 0/427 (0%) | 2/1507 (0.1%) | 1/1531 (0.1%) | |||
| Muscular weakness | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Arthropathy | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Bursitis | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Cervical spinal stenosis | 1/427 (0.2%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Intervertebral disc protrusion | 1/427 (0.2%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Pain in extremity | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Dupuytren's contracture | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Foot deformity | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Fracture pain | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Joint instability | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Joint range of motion decreased | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Muscle haemorrhage | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Musculoskeletal discomfort | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Myosclerosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Osteonecrosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pain in jaw | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Polymyalgia rheumatica | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Sacroiliitis | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Scoliosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Seronegative arthritis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Spinal osteoarthritis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Spondylolisthesis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Synovial cyst | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Tendon disorder | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Vertebral foraminal stenosis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Vertebral osteophyte | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Prostate cancer | 1/427 (0.2%) | 8/1507 (0.5%) | 5/1531 (0.3%) | |||
| Breast cancer | 2/427 (0.5%) | 2/1507 (0.1%) | 4/1531 (0.3%) | |||
| Pancreatic carcinoma | 1/427 (0.2%) | 3/1507 (0.2%) | 1/1531 (0.1%) | |||
| Malignant melanoma | 0/427 (0%) | 0/1507 (0%) | 4/1531 (0.3%) | |||
| Bladder cancer | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Bladder transitional cell carcinoma | 1/427 (0.2%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Diffuse large B-cell lymphoma | 0/427 (0%) | 0/1507 (0%) | 3/1531 (0.2%) | |||
| Invasive ductal breast carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Lung neoplasm malignant | 1/427 (0.2%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Adenocarcinoma of colon | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Adenocarcinoma pancreas | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Endometrial cancer | 2/427 (0.5%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Lung adenocarcinoma | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Lymphoma | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Malignant melanoma in situ | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Non-small cell lung cancer | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Parathyroid tumour benign | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Rectal adenocarcinoma | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Squamous cell carcinoma of lung | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Anal squamous cell carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Basal cell carcinoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Benign neoplasm of thyroid gland | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Benign renal neoplasm | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Bladder cancer stage 0, with cancer in situ | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Brain neoplasm | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Breast cancer in situ | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Cardiac myxoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Cholangiocarcinoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Choroid plexus papilloma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Colon cancer | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Colon cancer stage II | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Endometrial adenocarcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Follicular thyroid cancer | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Gastrointestinal carcinoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Glioma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Intracranial meningioma malignant | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Invasive papillary breast carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Large intestine benign neoplasm | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Laryngeal squamous cell carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lung adenocarcinoma stage II | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lung cancer metastatic | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lung carcinoma cell type unspecified stage IV | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Mantle cell lymphoma recurrent | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Metastatic malignant melanoma | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Mucinous breast carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Myelodysplastic syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Non-Hodgkin's lymphoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Non-small cell lung cancer stage IIIB | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Oesophageal adenocarcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Oesophageal carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Oesophageal squamous cell carcinoma | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Ovarian adenoma | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Papillary cystadenoma lymphomatosum | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Penile squamous cell carcinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Pituitary tumour benign | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Plasma cell myeloma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Plasmacytoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Polycythaemia vera | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Rectal cancer | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Renal cancer | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Schwannoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Spinal cord neoplasm | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Squamous cell carcinoma of skin | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Squamous cell carcinoma of the tongue | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Tongue neoplasm malignant stage unspecified | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Tonsil cancer | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Uterine cancer | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Uterine leiomyoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Nervous system disorders | ||||||
| Syncope | 2/427 (0.5%) | 13/1507 (0.9%) | 14/1531 (0.9%) | |||
| Transient ischaemic attack | 0/427 (0%) | 11/1507 (0.7%) | 10/1531 (0.7%) | |||
| Cerebrovascular accident | 1/427 (0.2%) | 10/1507 (0.7%) | 6/1531 (0.4%) | |||
| Presyncope | 1/427 (0.2%) | 4/1507 (0.3%) | 1/1531 (0.1%) | |||
| Carotid artery stenosis | 0/427 (0%) | 2/1507 (0.1%) | 3/1531 (0.2%) | |||
| Dizziness | 0/427 (0%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Ischaemic stroke | 0/427 (0%) | 1/1507 (0.1%) | 3/1531 (0.2%) | |||
| Cerebral haemorrhage | 0/427 (0%) | 3/1507 (0.2%) | 0/1531 (0%) | |||
| Seizure | 1/427 (0.2%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Generalised tonic-clonic seizure | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Intracranial aneurysm | 0/427 (0%) | 0/1507 (0%) | 2/1531 (0.1%) | |||
| Somnolence | 1/427 (0.2%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Transient global amnesia | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Amnesia | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Aphasia | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Carpal tunnel syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Cerebral infarction | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Dizziness postural | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Encephalopathy | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Facial neuralgia | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Facial paralysis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Haemorrhage intracranial | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Haemorrhagic stroke | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| IIIrd nerve paralysis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lacunar infarction | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lacunar stroke | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Metabolic encephalopathy | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Nerve compression | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Paraplegia | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Parkinson's disease | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Sciatica | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Spinal cord compression | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Temporal lobe epilepsy | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Product Issues | ||||||
| Device dislocation | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Psychiatric disorders | ||||||
| Mental status changes | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Alcohol abuse | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Alcohol withdrawal syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Confusional state | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Delirium | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Panic attack | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Suicidal ideation | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Renal and urinary disorders | ||||||
| Acute kidney injury | 3/427 (0.7%) | 5/1507 (0.3%) | 7/1531 (0.5%) | |||
| Urinary retention | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Haematuria | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Nephrolithiasis | 0/427 (0%) | 1/1507 (0.1%) | 2/1531 (0.1%) | |||
| Urinary tract obstruction | 1/427 (0.2%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Renal failure | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Urinary incontinence | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Calculus bladder | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Chronic kidney disease | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Diabetic nephropathy | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lower urinary tract symptoms | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Urethral obstruction | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Urethral stenosis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Urinoma | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Reproductive system and breast disorders | ||||||
| Benign prostatic hyperplasia | 2/427 (0.5%) | 4/1507 (0.3%) | 2/1531 (0.1%) | |||
| Prostatitis | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Prostatomegaly | 1/427 (0.2%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Vaginal prolapse | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Acquired hydrocele | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Prostatic haemorrhage | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Uterine prolapse | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Uterovaginal prolapse | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Vaginal haemorrhage | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Pulmonary embolism | 1/427 (0.2%) | 9/1507 (0.6%) | 11/1531 (0.7%) | |||
| Pulmonary hypertension | 2/427 (0.5%) | 6/1507 (0.4%) | 1/1531 (0.1%) | |||
| Chronic obstructive pulmonary disease | 0/427 (0%) | 4/1507 (0.3%) | 3/1531 (0.2%) | |||
| Dyspnoea | 1/427 (0.2%) | 2/1507 (0.1%) | 3/1531 (0.2%) | |||
| Pulmonary fibrosis | 1/427 (0.2%) | 1/1507 (0.1%) | 4/1531 (0.3%) | |||
| Asthma | 1/427 (0.2%) | 3/1507 (0.2%) | 0/1531 (0%) | |||
| Pneumothorax | 0/427 (0%) | 3/1507 (0.2%) | 1/1531 (0.1%) | |||
| Respiratory failure | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Acute respiratory failure | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Bronchiectasis | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Cough | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Interstitial lung disease | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Pleural effusion | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Pulmonary oedema | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Idiopathic pulmonary fibrosis | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Lung disorder | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Pulmonary granuloma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Skin and subcutaneous tissue disorders | ||||||
| Angioedema | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Precancerous skin lesion | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Surgical and medical procedures | ||||||
| Shoulder arthroplasty | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Vascular disorders | ||||||
| Deep vein thrombosis | 1/427 (0.2%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Hypotension | 1/427 (0.2%) | 4/1507 (0.3%) | 1/1531 (0.1%) | |||
| Aortic stenosis | 0/427 (0%) | 3/1507 (0.2%) | 2/1531 (0.1%) | |||
| Aortic aneurysm | 0/427 (0%) | 2/1507 (0.1%) | 2/1531 (0.1%) | |||
| Hypertension | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Peripheral artery occlusion | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Peripheral artery stenosis | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Peripheral vascular disorder | 0/427 (0%) | 1/1507 (0.1%) | 1/1531 (0.1%) | |||
| Varicose vein | 0/427 (0%) | 2/1507 (0.1%) | 0/1531 (0%) | |||
| Arteriosclerosis | 1/427 (0.2%) | 0/1507 (0%) | 0/1531 (0%) | |||
| Haematoma | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Hypertensive crisis | 0/427 (0%) | 0/1507 (0%) | 1/1531 (0.1%) | |||
| Orthostatic hypotension | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Superior mesenteric artery syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
| Superior vena cava syndrome | 0/427 (0%) | 1/1507 (0.1%) | 0/1531 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Low Risk Placebo | High Risk Placebo | High Risk Pioglitazone | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 235/427 (55%) | 828/1507 (54.9%) | 822/1531 (53.7%) | |||
| Eye disorders | ||||||
| Cataract | 27/427 (6.3%) | 119/1507 (7.9%) | 106/1531 (6.9%) | |||
| Gastrointestinal disorders | ||||||
| Constipation | 24/427 (5.6%) | 70/1507 (4.6%) | 72/1531 (4.7%) | |||
| Infections and infestations | ||||||
| Upper respiratory tract infection | 62/427 (14.5%) | 190/1507 (12.6%) | 183/1531 (12%) | |||
| Urinary tract infection | 47/427 (11%) | 178/1507 (11.8%) | 191/1531 (12.5%) | |||
| Nasopharyngitis | 22/427 (5.2%) | 72/1507 (4.8%) | 90/1531 (5.9%) | |||
| Sinusitis | 22/427 (5.2%) | 67/1507 (4.4%) | 52/1531 (3.4%) | |||
| Injury, poisoning and procedural complications | ||||||
| Fall | 18/427 (4.2%) | 143/1507 (9.5%) | 135/1531 (8.8%) | |||
| Musculoskeletal and connective tissue disorders | ||||||
| Arthralgia | 45/427 (10.5%) | 125/1507 (8.3%) | 125/1531 (8.2%) | |||
| Back pain | 31/427 (7.3%) | 82/1507 (5.4%) | 101/1531 (6.6%) | |||
| Osteoarthritis | 19/427 (4.4%) | 81/1507 (5.4%) | 86/1531 (5.6%) | |||
| Neoplasms benign, malignant and unspecified (incl cysts and polyps) | ||||||
| Basal cell carcinoma | 23/427 (5.4%) | 59/1507 (3.9%) | 71/1531 (4.6%) | |||
| Respiratory, thoracic and mediastinal disorders | ||||||
| Cough | 20/427 (4.7%) | 79/1507 (5.2%) | 76/1531 (5%) | |||
| Vascular disorders | ||||||
| Hypertension | 26/427 (6.1%) | 97/1507 (6.4%) | 93/1531 (6.1%) | |||
Limitations/Caveats
[Not Specified]
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
The first study related publication will be a multi-center publication submitted within 24 months after conclusion or termination of a study at all sites. After such multi site publication, all proposed site publications and presentations will be submitted to sponsor for review 60 days in advance of publication. Site will remove Sponsor confidential information unrelated to study results. Sponsor can delay a proposed publication for another 60 days to preserve intellectual property.
Results Point of Contact
| Name/Title | Medical Director |
|---|---|
| Organization | Takeda |
| Phone | +1-877-825-3327 |
| trialdisclosures@takeda.com |
Responsible Party:
Takeda
ClinicalTrials.gov Identifier:
NCT01931566
Other Study ID Numbers:
- AD-4833/TOMM40_301
- 2012-003111-58
- U1111-1139-0355
First Posted:
Aug 29, 2013
Last Update Posted:
Sep 16, 2019
Last Verified:
Aug 1, 2019