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| ID | Type | Description | Link |
|---|---|---|---|
| U1111-1132-3482 | Registry Identifier | WHO |
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| Name | Class |
|---|---|
| Kaiser Permanente | OTHER |
| Department of Epidemiology at University of Pennsylvania | UNKNOWN |
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To assess the potential association between pioglitazone and bladder cancer compared with non-pioglitazone users among patients with type 2 diabetes mellitus.
Following guidance from the United States Food and Drug Administration (FDA) and European Medicines Agency, the University of Pennsylvania and Kaiser Permanente Northern California (KPNC) designed and conducted this study using the KPNC database to assess the potential association between pioglitazone and bladder cancer among patients with type 2 diabetes mellitus.
The study was conducted over the course of 10 years, with a series of interim analyses undertaken during this period and provided to the sponsor (Takeda) and the appropriate regulatory agencies.
In 2011, the planned 5-year interim analysis of this study was published in Diabetes Care. That report included data from 1 January 1997 to 30 April 2008. Following reporting of these data, there was a request from the FDA for an additional fourth interim analysis at 8 years including data from 1 January 1997 to 31 December 2010.
In August 2011 the FDA requested inclusion of a sensitivity analysis to assess change of cohort entry criteria to minimize left censoring of exposure. Included in the FDA request was a duration analysis for other antidiabetic medications.
In August 2014, the final 10-year analyses were completed and submitted to the sponsor and regulatory agencies.
Interim results previously posted on clinicaltrials.gov are available in the public archive
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Pioglitazone exposed group | Defined as those patients having filled at least two prescriptions for pioglitazone within a 6-month period. Patients in the pioglitazone group may also have exposure to other diabetic medications |
| |
| Pioglitazone unexposed group | Defined as patients who did not fill at least two prescriptions for pioglitazone within a 6-month period. Patients in the pioglitazone unexposed group may have been exposed to other diabetic medications. This group also included diabetic patients without any diabetic medications. |
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Pioglitazone | Drug | Pioglitazone tablets. |
|
| Measure | Description | Time Frame |
|---|---|---|
| Incident Diagnosis of Bladder Cancer (10-year Analysis) | Incident bladder cancers were identified from January 1, 1997 to December 31, 2012. | January 1, 1997 to December 31, 2012 |
| Measure | Description | Time Frame |
|---|---|---|
| Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | January 1, 1997 to December 31, 2012 | |
| Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
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Inclusion Criteria:
The study cohort included both patients with an established diagnosis of diabetes mellitus prior to January 1, 1997 and those who were newly diagnosed prior to December 31, 2002. Patients were eligible for the study cohort if they met any of the following criteria:
As of January 1, 1997 they had been diagnosed with diabetes mellitus, were age 40 or older and were members of KPNC,
They had been diagnosed with diabetes mellitus, reached age 40 between January 1, 1997 and December 31, 2002 and were KPNC members on their 40th birthday, or
Had diabetes mellitus and were age 40 or older when they joined KPNC between January 1, 1997 and December 31, 2002.
Exclusion Criteria:
Diagnosis of bladder cancer recorded in the KPNC cancer registry prior to entry to the cohort or within 6 months of entry into KPNC.
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The study was conducted within Kaiser Permanente Northern California (KPNC), which provides comprehensive healthcare services to approximately 3.2 million members. The source population was identified from the KPNC diabetes registry, which was first constructed in 1993 and has been updated annually since then. The registry identifies patients primarily from four data sources: primary hospital discharge diagnoses of diabetes mellitus (since 1971); two or more outpatient visit diagnoses of diabetes (since 1995); any prescription for a diabetes-related medication (since 1994); or any record of an abnormal hemoglobin A1c (HbA1c) test (>6.7%) (since 1991).
The diabetes registry gathers data from a variety of KPNC electronic medical records (EMR) to build and follow the registry cohort across time. These data include cancer registries, pharmacy records, laboratory records, and inpatient and outpatient medical diagnoses.
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 21447663 | Result | Lewis JD, Ferrara A, Peng T, Hedderson M, Bilker WB, Quesenberry CP Jr, Vaughn DJ, Nessel L, Selby J, Strom BL. Risk of bladder cancer among diabetic patients treated with pioglitazone: interim report of a longitudinal cohort study. Diabetes Care. 2011 Apr;34(4):916-22. doi: 10.2337/dc10-1068. | |
| 26197187 | Result |
| Label | URL |
|---|---|
| ACTOS® Package Insert | View source |
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Not applicable (database study)
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| ID | Title | Description |
|---|---|---|
| FG000 | Pioglitazone Exposed Group | Patients ever exposed to pioglitazone. |
| FG001 | Pioglitazone Unexposed Group | Patients never exposed to pioglitazone. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Pioglitazone Exposed Group | Patients ever exposed to pioglitazone. |
| BG001 | Pioglitazone Unexposed Group | Patients never exposed to pioglitazone. |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Customized | Number |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | |||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | Incident Diagnosis of Bladder Cancer (10-year Analysis) | Incident bladder cancers were identified from January 1, 1997 to December 31, 2012. | All participants. | Posted | Number | 95% Confidence Interval | events per 100,000 person years | January 1, 1997 to December 31, 2012 |
|
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Adverse events not applicable as this study is based on the secondary use of electronic medical records.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Pioglitazone Exposed Group | Patients ever exposed to pioglitazone. |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Head, Pharmacoepidemiology | Takeda | +1-877-825-3327 | trialdisclosures@takeda.com |
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| ID | Term |
|---|---|
| D003920 | Diabetes Mellitus |
| D001749 | Urinary Bladder Neoplasms |
| ID | Term |
|---|---|
| D044882 | Glucose Metabolism Disorders |
| D008659 | Metabolic Diseases |
| D009750 | Nutritional and Metabolic Diseases |
| D004700 | Endocrine System Diseases |
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| ID | Term |
|---|---|
| D000077205 | Pioglitazone |
| ID | Term |
|---|---|
| D045162 | Thiazolidinediones |
| D013844 | Thiazoles |
| D013457 | Sulfur Compounds |
| D009930 | Organic Chemicals |
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| Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
| Stage of Bladder Cancer (10 Year Analysis) | January 1, 1997 to December 31, 2012 |
| Lewis JD, Habel LA, Quesenberry CP, Strom BL, Peng T, Hedderson MM, Ehrlich SF, Mamtani R, Bilker W, Vaughn DJ, Nessel L, Van Den Eeden SK, Ferrara A. Pioglitazone Use and Risk of Bladder Cancer and Other Common Cancers in Persons With Diabetes. JAMA. 2015 Jul 21;314(3):265-77. doi: 10.1001/jama.2015.7996. |
| BG002 | Total | Total of all reporting groups |
| percentage of participants |
|
| Sex/Gender, Customized | Number | percentage of participants |
|
| Race/Ethnicity, Customized | Number | percentage of participants |
|
| Current smoker | Number | percentage of participants |
|
| Renal function at baseline | Elevated creatinine: Creatinine >1.4 mg/dL for women and >1.5 mg/dL for men. | Number | percentage of participants |
|
| Congestive heart failure at baseline | Number | percentage of participants |
|
| Baseline Glycosylated Hemoglobin (HbA1c) | Number | percentage of participants |
|
| Newly diagnosed with diabetes mellitus at the start of follow-up | Includes newly diagnosed patients and patients who newly enrolled in Kaiser Permanente with an existing diagnosis of diabetes mellitus. | Number | percentage of participants |
|
| Diabetes duration at baseline | Number | percentage of participants |
|
| Other cancer prior to baseline | Number | percentage of participants |
|
| Other diabetes medications | Includes use of any other diabetes medications during follow-up. | Number | percentage of participants |
|
| Units | Counts |
|---|
| Participants |
|
|
|
| Secondary | Incident Diagnosis of Bladder Cancer by Time Since Starting Pioglitazone (10 Year Analysis) | Posted | Number | 95% Confidence Interval | events per 100,000 person years | January 1, 1997 to December 31, 2012 |
|
|
|
|
| Secondary | Incident Diagnosis of Bladder Cancer by Duration of Pioglitazone Therapy (10 Year Analysis) | All participants. | Posted | Number | 95% Confidence Interval | events per 100,000 person years | January 1, 1997 to December 31, 2012 |
|
|
|
|
| Secondary | Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone (10 Year Analysis) | All participants. | Posted | Number | 95% Confidence Interval | events per 100,000 person years | January 1, 1997 to December 31, 2012 |
|
|
|
|
| Secondary | Stage of Bladder Cancer (10 Year Analysis) | Participants diagnosed with bladder cancer. | Posted | Number | percentage of participants | January 1, 1997 to December 31, 2012 |
|
|
|
| 0 |
| 0 |
| 0 |
| 0 |
| EG001 | Pioglitazone Unexposed Group | Patients never exposed to pioglitazone. | 0 | 0 | 0 | 0 |
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 45 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.
| D014571 | Urologic Neoplasms |
| D014565 | Urogenital Neoplasms |
| D009371 | Neoplasms by Site |
| D009369 | Neoplasms |
| D052776 | Female Urogenital Diseases |
| D005261 | Female Urogenital Diseases and Pregnancy Complications |
| D000091642 | Urogenital Diseases |
| D001745 | Urinary Bladder Diseases |
| D014570 | Urologic Diseases |
| D052801 | Male Urogenital Diseases |
| D001393 |
| Azoles |
| D006573 | Heterocyclic Compounds, 1-Ring |
| D006571 | Heterocyclic Compounds |
| More than 8.0 years |
|
| Time since starting pioglitazone 4.5-8 years vs unexposed group. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.21 | 95 | 0.93 | 1.59 | Superiority or Other |
| Time since starting pioglitazone >8 years vs unexposed group. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.20 | 95 | 0.83 | 1.75 | Superiority or Other |
| More than 4 years |
|
| Duration of therapy 1.5-4 years. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.03 | 95 | 0.80 | 1.33 | Superiority or Other |
| Duration of therapy >4 years. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.16 | 95 | 0.87 | 1.54 | Superiority or Other |
| >40000 mg |
|
| Cumulative dose 14001-40000 mg. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.10 | 95 | 0.85 | 1.42 | Superiority or Other |
| Cumulative dose >40000 mg. Fully adjusted including all potential confounders in statistical model from 5-year interim report plus year of cohort entry: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder, renal insufficiency, HbA1c and interaction with new diagnosis of diabetes, duration of diabetes, year of cohort entry and proteinuria. | Hazard Ratio (HR) | 1.07 | 95 | 0.79 | 1.44 | Superiority or Other |
| Local |
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| Regional |
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| Distant |
|
| Undetermined |
|