Cohort Study of Pioglitazone and Bladder Cancer in Patients With Type II Diabetes

This study is ongoing, but not recruiting participants.
Sponsor:
Collaborator:
Kaiser Permanente
Information provided by (Responsible Party):
Takeda
ClinicalTrials.gov Identifier:
NCT01637935
First received: July 7, 2012
Last updated: June 19, 2013
Last verified: June 2013
  Purpose

To assess the potential association between pioglitazone and bladder cancer compared with non-pioglitazone users among patients with type 2 diabetes mellitus.


Condition Intervention
Diabetes
Bladder Cancer
Drug: Pioglitazone

Study Type: Observational
Study Design: Observational Model: Cohort
Time Perspective: Retrospective
Official Title: Cohort Study of Pioglitazone and Bladder Cancer in Patients With Diabetes

Resource links provided by NLM:


Further study details as provided by Takeda:

Primary Outcome Measures:
  • Incident Diagnosis of Bladder Cancer Identified From the Kaiser Permanente Northern California Cancer Registry From 01 January 1997 to 31 December 2010. [ Time Frame: January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]
    Incident bladder cancers were identified from the KPNC cancer registry from January 1, 1997 to December 31, 2010. This was supplemented by case identification through surveillance of electronic pathology reports within KPNC for the period from January 1, 2005 to December 31, 2010. Incidence is reported as the number of newly diagnosed cases of bladder cancer per 100,000 person years. The 95% confidence interval was calculated using the Poisson method.


Secondary Outcome Measures:
  • Incident Diagnosis of Bladder Cancer, by Time Since Starting Pioglitazone [ Time Frame: January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]
    Incident bladder cancers were identified from the KPNC cancer registry from January 1, 1997 to December 31, 2010. This was supplemented by case identification through surveillance of electronic pathology reports within KPNC for the period from January 1, 2005 to December 31, 2010. Incidence is reported as the number of newly diagnosed cases of bladder cancer per 100,000 person years by time since starting pioglitazone. The 95% confidence interval was calculated using the Poisson method.

  • Incident Diagnosis of Bladder Cancer, by Duration of Pioglitazone Therapy [ Time Frame: January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]
    Incident bladder cancers were identified from the KPNC cancer registry from January 1, 1997 to December 31, 2010. This was supplemented by case identification through surveillance of electronic pathology reports within KPNC for the period from January 1, 2005 to December 31, 2010. Incidence is reported as the number of newly diagnosed cases of bladder cancer per 100,000 person years and by duration of pioglitazone therapy. The 95% confidence interval was calculated using the Poisson method.

  • Incident Diagnosis of Bladder Cancer by Cumulative Dose of Pioglitazone [ Time Frame: January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]
    Incident bladder cancers were identified from the KPNC cancer registry from January 1, 1997 to December 31, 2010. This was supplemented by case identification through surveillance of electronic pathology reports within KPNC for the period from January 1, 2005 to December 31, 2010. Incidence is reported as the number of newly diagnosed cases of bladder cancer per 100,000 person years by cumulative dose of pioglitazone. The 95% confidence interval was calculated using the Poisson method.

  • Participants With Bladder Cancer by Stage of Cancer [ Time Frame: January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]
    Incident bladder cancers were identified from the KPNC cancer registry from January 1, 1997 to December 31, 2010. This was supplemented by case identification through surveillance of electronic pathology reports within KPNC for the period from January 1, 2005 to December 31, 2010. Bladder cancer stages are: PUNLMP (Papillary urethral neoplasm of low malignant potential); In situ (cancer is growing in the inner lining layer of the bladder only); Local (cancer has grown into the thick muscle layer of the bladder wall, but it has not passed completely through the muscle to reach the layer of fatty tissue that surrounds the bladder); Regional (cancer has grown through the bladder wall and into the pelvic or abdominal wall but has not spread to lymph nodes or to distant sites); Distant (cancer has spread to distant sites such as bones, liver, or lungs); Undetermined.

  • Comparison of the Results of the Current Analysis and the 5-Year Interim Report for Incidence of Bladder Cancer [ Time Frame: The 5-year analysis includes data from January 1 1997 to 30 April 2008. The 8-year analysis includes data from January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]

    Data presented are the hazard ratios for comparison of the group of participants treated with pioglitazone with those who received no pioglitazone therapy. Cox proportional hazards models were used for all calculations of the relative hazard (HR) of bladder cancer with pioglitazone, adjusted for the covariates. The reference group for calculation of the relative hazard associated with use of pioglitazone was no use of pioglitazone.

    The fully adjusted includes all potential confounders in the statistical model from the 5 year interim report: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder cancer, renal insufficiency, HbA1c and the interaction with new diagnosis of diabetes, and duration of diabetes. In the 8 year analysis, the fully adjusted model also includes year of cohort entry.


  • Comparison of the Results of the Current Analysis and the 5-Year Interim Report for Incidence of Bladder Cancer, by Time Since Starting Pioglitazone [ Time Frame: The 5-year analysis includes data from January 1 1997 to 30 April 2008. The 8-year analysis includes data from January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]

    Data presented are the hazard ratios for comparison of the participants treated with pioglitazone, by time since starting pioglitazone with those who received no pioglitazone. Cox proportional hazards models were used for all calculations of the relative hazard (HR) of bladder cancer with pioglitazone, adjusted for the covariates.

    The fully adjusted model includes all potential confounders in the statistical model from the 5 year interim report: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder cancer, renal insufficiency, HbA1c and the interaction with new diagnosis of diabetes, and duration of diabetes. In the 8 year analysis, the fully adjusted model also includes year of cohort entry.

    Row headings state the equivalent number of years since starting pioglitazone therapy first for the 5 year analysis and then for the 8-year analysis.


  • Comparison of the Results of the Current Analysis and the 5-Year Interim Report for Incidence of Bladder Cancer, by Duration of Therapy [ Time Frame: The 5-year analysis includes data from January 1 1997 to 30 April 2008. The 8-year analysis includes data from January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]

    Data presented are the hazard ratios for comparison of the participants treated with pioglitazone, by duration of pioglitazone therapy with those who received no pioglitazone. Cox proportional hazards models were used for all calculations of the relative hazard (HR) of bladder cancer with pioglitazone, adjusted for the covariates.

    The fully adjusted model includes all potential confounders in the statistical model from the 5 year interim report: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder cancer, renal insufficiency, HbA1c and the interaction with new diagnosis of diabetes, and duration of diabetes. In the 8 year analysis, the fully adjusted model also includes year of cohort entry.

    Row headings state the number of years of duration of therapy first for the 5 year analysis and then the equivalent duration of therapy for the 8-year analysis.


  • Comparison of the Results of the Current Analysis and the 5-Year Interim Report for Incidence of Bladder Cancer, by Cumulative Dose [ Time Frame: The 5-year analysis includes data from January 1 1997 to 30 April 2008. The 8-year analysis includes data from January 1, 1997 to December 31, 2010. ] [ Designated as safety issue: Yes ]

    Data presented are the hazard ratios for comparison of the participants treated with pioglitazone, by cumulative dose of pioglitazone with those who received no pioglitazone. Cox proportional hazards models were used for all calculations of the relative hazard (HR) of bladder cancer with pioglitazone, adjusted for the covariates.

    The fully adjusted model includes all potential confounders in the statistical model from the 5 year interim report: age, sex, race/ethnicity, other diabetes medications, smoking, other bladder conditions, median household income, congestive heart failure, cancer other than bladder cancer, renal insufficiency, HbA1c and the interaction with new diagnosis of diabetes, and duration of diabetes. In the 8 year analysis, the fully adjusted model also includes year of cohort entry.

    Row headings state the cumulative pioglitazone dose first for the 5-Year analysis and then the equivalent cumulative dose for the 8-Year analysis.



Enrollment: 200000
Study Start Date: July 2004
Estimated Study Completion Date: December 2013
Estimated Primary Completion Date: December 2013 (Final data collection date for primary outcome measure)
Groups/Cohorts Assigned Interventions
Pioglitazone treated
Participants treated with pioglitazone, defined as having filled at least two prescriptions for the drug within a 6-month period according to the Kaiser Permanente Northern California (KPNC) pharmacy database.
Drug: Pioglitazone
Pioglitazone tablets.
Other Name: Actos
No pioglitazone treatment
Participants not treated with pioglitazone, defined as not having filled at least two prescriptions for the drug within a 6-month period according to the KPNC pharmacy database.

Detailed Description:

Following guidance from the United States Food and Drug Administration (FDA), the University of Pennsylvania and Kaiser Permanente Northern California (KPNC) designed and is conducting this study from their own database to assess the potential association between pioglitazone and bladder cancer among patients with type 2 diabetes mellitus.

The study is being conducted over the course of 10 years, with a series of interim analyses 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 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.

  Eligibility

Ages Eligible for Study:   40 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Sampling Method:   Probability Sample
Study Population

The study is being 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.

Criteria

Inclusion Criteria:

  • In the KPNC diabetes registry and who are age 40 or older as of January 1, 1997 or additional registry members who reach age 40 at any point before December 31 2002; patients age 40 or older who enroll in KPNC between January 1, 1997 and December 21 2002 and who are identified as having diabetes; and all KP members age 40 or older who develop diabetes during this time period.

Inclusion Criteria for the Sensitivity Analysis - Modified Cohort:

  • All patients who are in the KPNC Diabetes Registry and who are age 40 or older as of January 1, 1997;
  • All additional KPNC Diabetes Registry members who reach age 40 at any point before December 31, 2009 and who have been enrolled in KPNC since January 1, 1997 without a gap in membership;
  • All KPNC members age 40 or older who are newly diagnosed with diabetes between January 1, 1997 and December 31, 2009. The definition of newly diagnosed diabetes requires that the patient be a KPNC member for more than 2 years before being identified as having diabetes according the registry criteria.

Exclusion Criteria:

  • Diagnosis of bladder cancer recorded in the KPNC cancer registry prior to initiation of observation or within 6 months of entry into KPNC.

Inclusion Criteria for the Sensitivity Analysis - Modified Cohort:

  • all patients who are in the KPNC Diabetes Registry and who are age 40 or older as of January 1, 1997;
  • all additional KPNC Diabetes Registry members who reach age 40 at any point before December 31, 2009 and who have been enrolled in KPNC since January 1, 1997 without a gap in membership;
  • all KPNC members age 40 or older who are newly diagnosed with diabetes between January 1, 1997 and December 31, 2009. The definition of newly diagnosed diabetes requires that the patient be a KPNC member for more than 2 years before being identified as having diabetes according the registry criteria.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

No Contacts or Locations Provided
  More Information

Additional Information:
Publications:
Responsible Party: Takeda
ClinicalTrials.gov Identifier: NCT01637935     History of Changes
Other Study ID Numbers: 01-03-TL-OPI-524, U1111-1132-3482
Study First Received: July 7, 2012
Results First Received: August 31, 2012
Last Updated: June 19, 2013
Health Authority: United States: Food and Drug Administration

Keywords provided by Takeda:
Drug therapy

Additional relevant MeSH terms:
Urinary Bladder Neoplasms
Diabetes Mellitus
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Neoplasms
Urinary Bladder Diseases
Urologic Diseases
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Pioglitazone
Hypoglycemic Agents
Physiological Effects of Drugs
Pharmacologic Actions

ClinicalTrials.gov processed this record on July 22, 2014