AzTrials
AzTrials

Diabetes MellitusPhase 4NCT00494312

Safety Study of Pioglitazone Compared To Glyburide on Liver Function

A Phase 4 study testing Pioglitazone and Glyburide in people with Diabetes Mellitus and Liver, run by Takeda.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

The purpose of this study is to determine the liver safety of pioglitazone, once daily (QD), versus glyburide taken with metformin and insulin. Read more about this study

Who is it for?
Ages 18 to 80 years
Conditions the study is for
Diabetes Mellitus, Liver
What is being tested?
Pioglitazone and Glyburide
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
2,120 participants
Where
No sites listed yet
Study dates
Oct 2000to Jun 2005
Phase
Phase 4
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 to 80 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Females of childbearing potential who are sexually active must agree to use adequate contraception, and can neither be pregnant nor lactating from Screening throughout the duration of the study
  • Diagnosis of type 2 (non-insulin dependent) diabetes mellitus as defined by the diagnostic criteria of the American Diabetes Association and currently taking glyburide, glipizide, glimepiride, or metformin alone, or glyburide, glipizide, or glimepiride in combination with metformin
  • Glycosylated hemoglobin level greater than or equal to 7.0%
  • Fasting C-peptide level greater than or equal to 0.7 ng/mL.

Who cannot join

  • Type 1 (insulin-dependent) diabetes mellitus.
  • Prior exposure to a thiazolidinedione, except subjects who discontinued use of troglitazone in March or April of 2000, provided they were not experiencing adverse effects and were not then taking thiazolidinediones.
  • Participating in another investigational study or had participated in an investigational trial within the preceding 2 months.
  • History of ketoacidosis.
  • The subject had significant diabetic nephropathy, defined as a serum creatinine level greater than or equal to 1.5 mg/dL for men and greater than or equal to 1.4 mg/dL for women, or urinary protein excretion greater than or equal to 2 plus as measured by the Combistix (or equivalent) method, except subjects with proteinuria are eligible if repeat testing within 2 weeks indicates the proteinuria had resolved.
  • Anemia with a hemoglobin level less than12 g/dL for men and less than10 g/dL for women.
Show all 24Show fewer
  • The subject had a history of drug or alcohol abuse within the preceding 2 years.
  • The subject had a diastolic blood pressure greater than100 mm Hg or a systolic blood pressure greater than180 mm Hg.
  • The subject had evidence of ongoing cardiac rhythm disturbance, delayed QT waves, or second-degree atrioventricular heart block. Uncomplicated first-degree atrioventricular block was allowed.
  • Significant cardiovascular disease including, but not limited to, New York Heart Association Functional (Cardiac) Classification III or IV.
  • History of myocardial infarction, acute cardiovascular event, or cerebrovascular accident within the preceding 6 months.
  • Previous history of cancer that was not in remission for at least 5 years before administration of the first dose of study drug. Except, basal cell or Stage I squamous cell carcinoma.
  • The subject had a BMI less than 20 or greater than 48 (calculated as weight [kg]/height [m2]).
  • Alanine aminotransferase level greater than or equal 2.5time the upper limit of normal or a history of liver disease, jaundice, hepatitis, or biliary tract disease (except for uncomplicated and treated gall stones by either lithotomy or cholecystectomy).
  • Unwilling or unable to comply with the protocol or attend scheduled appointments.
  • Unable to understand verbal and/or written English or any other language in which a certified translation of the informed consent is available.
  • Evidence of acute or unstable chronic pulmonary disease or, if a chest x-ray was available, has unexplained pulmonary lesions.
  • Is required to take or continues taking any disallowed medication, prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
  • Antidiabetic agents other than study drug and companion medications (metformin and insulin).
  • Weight loss agents, including pharmaceuticals and over-the-counter brands.
  • Continuous (greater than 2 weeks) steroid therapy or expected recurrent steroid therapy, including all injectable, inhaled, topical, and oral steroid formulations.
  • Niacin therapy.
  • Chronic condition for which the recurrent use of glucocorticoids could be expected
  • Any other serious disease or condition at screening or randomization that might have affected life expectancy or made it difficult to successfully manage and follow the subject according to the protocol.

About this study

Official title: A Randomized, Comparator Controlled, Double-Blind Study of the Liver Safety of Pioglitazone HCl vs Glyburide With Metformin and Insulin as Part of Step Therapy in Subjects With Type 2 (Non-Insulin Dependent) Diabetes

The purpose of this study is to determine the liver safety of pioglitazone, once daily (QD), versus glyburide taken with metformin and insulin.

Read the detailed description

Type 2 diabetes generally arises from an initial state of insulin resistance that coincides with a gradual decline in insulin secretion due to beta-cell dysfunction. Together, these factors contribute to impaired glucose tolerance and eventually hyperglycemia.

Thiazolidinediones are selective agonists for the nuclear receptor peroxisomal proliferator-activated receptor gamma. These receptors are found in tissues with insulin action including adipose tissue, skeletal muscle and the liver. Thiazolidinediones reduce insulin resistance by enhancing insulin sensitivity in adipose tissue, muscle cells and hepatic cells without directly affecting insulin secretion. These effects improve glycemic control and result in reduced levels of circulating insulin.

Pioglitazone is a thiazolidinedione developed by Takeda Chemical Industries, Ltd., and depends on the presence of insulin for its mechanism of action. Glyburide is an oral antidiabetic agent of the sulfonylurea class, and impacts glycemic control by stimulating the pancreas to release insulin, an effect that is dependent upon beta-cells in the pancreatic islets.

Elevated levels of hepatic enzymes, hepatocellular inflammation, and viral susceptibility are known to occur with increased frequency in individuals with type 2 diabetes mellitus regardless of the type of antidiabetic therapy used. Subject to the approval of pioglitazone, the Food and Drug Administration requested a 3-year outcome study evaluating the occurrence of serious liver disease in subjects treated with pioglitazone. The present study was designed to fulfill this phase 4, postmarketing commitment to the Food and Drug Administration, pursuant to demonstrating the long-term hepatic safety of pioglitazone. This study was designed to determine whether pioglitazone is associated with a difference in the incidence of elevated levels of alanine aminotransferase, a marker of hepatocellular inflammation or injury, when compared with glyburide. Glyburide is used for treatment of patients with type 2 diabetes mellitus; its use in this study as a comparator should provide a basis for evaluating whether pioglitazone is associated with an increased risk of hepatocellular inflammation or injury.

Being tested
Pioglitazone, Glyburide
Keywords
Glucose Metabolism Disorder, Dysmetabolic Syndrome, Type II Diabetes, Diabetes Mellitus, Lipoatrophic, Dyslipidemia, Liver, Drug Therapy
Medical subject headings
Diabetes Mellitus, Glucose Metabolism Disorders, Diabetes Mellitus, Type 2, Dyslipidemias

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • PioglitazoneDrug

    Also called Actos, AD-4833

    Pioglitazone 15 mg or 30 mg titrated to 45 mg, tablets, orally, once daily and glyburide placebo-matching capsules, orally, once daily for up to 156 weeks.

  • GlyburideDrug

    Pioglitazone placebo-matching tablets, orally, once daily and glyburide 5 mg or 10 mg titrated to 15 mg, capsules, orally, once daily for up to 156 weeks.

Study groups in NCT00494312
Study groupRoleWhat they receive
Pioglitazone QDExperimentalNot described
Receives: Drug: Pioglitazone
Glyburide QDActive comparatorNot described
Receives: Drug: Glyburide

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Incidence of liver inflammation or injury greater than 3 times the upper limit of normal, as monitored by serum alanine aminotransaminase elevation.

    Measured: At All Visits

Secondary outcomes (4)

  1. Incidence of alanine aminotransferase greater than 8 times the upper limit of normal.

    Measured: At All Visits

  2. Incidence of alanine aminotransferase greater than 3 times the upper limit of normal but less than or equal to 8 times the upper limit of normal on 4 consecutive measurements within a 3-month period.

    Measured: At All Visits

  3. Incidence of alanine aminotransferase greater than 3 times the upper limit of normal and total bilirubin greater than 2 times the upper limit of normal.

    Measured: At All Visits

  4. Change from Baseline or greater than 1.5 times the upper limit of normal (whichever is greater) in the level of alanine aminotransferase, aspartate aminotransferase, total or direct bilirubin, alkaline phosphatase or gamma-glutamyl transpeptidase.

    Measured: At All Visits

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted29 Jun 2007 (estimated)
  2. Study startOct 2000
  3. Primary completionJun 2005
  4. Study completionJun 2005

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 4
Primary purpose
Treatment
Allocation
Randomised
Intervention model
Parallel groups
Masking
Quadruple blind
Who is masked
Participant, Care provider, Investigator, Outcomes assessor
Enrolment
2,120 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT00494312
Sponsor's protocol ID
01-00-TL-OPI-506
Other IDs
U1111-1114-1564
Status last verified
Feb 2012
First submitted
27 Jun 2007
Last updated
28 Feb 2012
Results posted
No
Data monitoring committee
Yes

Publications

  • Tolman KG, Fonseca V, Tan MH, Dalpiaz A. Narrative review: hepatobiliary disease in type 2 diabetes mellitus. Ann Intern Med. 2004 Dec 21;141(12):946-56. doi: 10.7326/0003-4819-141-12-200412210-00011.

    PubMed 15611492

  • Tolman KG, Freston JW, Kupfer S, Perez A. Liver safety in patients with type 2 diabetes treated with pioglitazone: results from a 3-year, randomized, comparator-controlled study in the US. Drug Saf. 2009;32(9):787-800. doi: 10.2165/11316510-000000000-00000.

    PubMed 19670918

Questions about this trial

What is this clinical trial studying?

A Phase 4 study testing Pioglitazone and Glyburide in people with Diabetes Mellitus and Liver, run by Takeda.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 4 inclusion and 24 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 28 Feb 2012. Status can change between updates, so confirm with the study contact before making plans.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of liver inflammation or injury greater than 3 times the upper limit of normal, as monitored by serum alanine aminotransaminase elevation. (time frame: At All Visits). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT00494312, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Feb 2012.

AzTrials uses cookies for analytics and advertising. You can accept or reject them; the site works either way. Privacy Policy.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in