Official Title: “Effect of Pioglitazone 15 mg or 30 mg on Microcirculation in Type 2 Diabetes Patients Treated With Insulin”

The purpose of this study is to measure microcirculation in type 2 diabetes patients with peripheral edema who are taking pioglitazone.

Study Type: Interventional

Study Design: Treatment, Randomized, Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Placebo Control, Parallel Assignment, Safety/Efficacy Study

Study Primary Completion Date: August 2004

Pioglitazone is a thiazolidinedione compound with a mode of action as a peroxisome proliferator-activated receptor gamma agonist. Activation of this receptor causes increased transcriptional activity at a number of locations that are important to carbohydrate and lipid (fat) metabolism. Insulin resistance is reversed by enhancing the action of insulin, thereby promoting glucose utilization in peripheral tissues, suppressing gluconeogenesis in the liver, and reducing lipolysis at the adipocyte.

In previous studies of pioglitazone, peripheral edema (swelling in the hands, feet, and legs) was reported as an adverse event more often in pioglitazone groups and appears to be a dose dependent phenomenon with pioglitazone. The incidence of peripheral edema in monotherapy studies was 3.2% in pioglitazone patients compared with 0.7% placebo patients and was reported more by females than males. This incidence was higher when pioglitazone was combined with sulphonylurea or insulin (5.9% and 15.6%, respectively). In comparison, the incidence of edema, when sulphonylurea or insulin was combined with placebo, was 2.1% and 7.5%, respectively.

This study is designed to identify the mechanisms underlying peripheral edema formation with pioglitazone in patients with Type 2 diabetes.

Individuals who participate in this study will provide written informed consent and will be required to commit to a screening visit and approximately 4 additional visits at the study center. Study participation is anticipated to be about 10 to 12 weeks (or approximately 3 months). Multiple procedures will occur at each visit which may include fasting, blood collection, urine collection, physical examinations and electrocardiograms.

Intervention(s) in this Clinical Trial

• Drug: Pioglitazone
  • Pioglitazone 15 mg to 30 mg, tablets, orally, once daily for up to 10 weeks
• Drug: Placebo
  • Pioglitazone placebo-matching tablets, orally, once daily for up to 10 weeks

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Capillary filtration capacity.
  • Time Frame: Final Visit
    Safety Issue?: No

Secondary Measures

• Isovolumetric venous pressure.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Capillary pressure.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Postural vasoconstriction.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Maximum blood flow.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Capillary recruitment.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• 24-hour ambulatory blood pressure.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Interleukin-6
  • Time Frame: Final Visit
    Safety Issue?: Yes
• C-Reactive Protein.
  • Time Frame: Final Visit
    Safety Issue?: Yes
• Vascular Endothelium Growth Factor.
  • Time Frame: Final Visit
    Safety Issue?: Yes

Inclusion Criteria:

• Stable glycemic control glycosylated hemoglobin between 6.5 and 10%) in the two months prior to the study.
• Type 2 diabetes treated by diet and stable dose of insulin (alone or with metformin) in the three months prior to the study.
• Female patients must have been postmenopausal, had a hysterectomy, or were surgically sterilized.

Exclusion Criteria:

• Has Type 1 diabetes.
• Has an episode of hypoglycemia requiring medical assistance three months prior to the study.
• Has peripheral artery disease (including Raynaud's syndrome) confirmed by an Ankle
• Brachial Pressure Index less than 0.9.
• Has severe chronic venous insufficiency as evidenced by venous ulceration or subcutaneous serum deposits.
• Has vascular autoimmune disease, had received a renal transplant, or were receiving dialysis.
• Has had heart failure (New York Heart Association I to IV), left ventricular hypertrophy evident from the ECG, or myocardial infarction 12 months prior to start of study.
• Has Subject had uncontrolled hypertension or familial polyposis coli.
• Is required to take or intends to continue taking any disallowed medication, any prescription medication, herbal treatment or over-the counter medication that may interfere with evaluation of the study medication, including:
• Non steroidal anti-inflammatory Drugs (except for aspirin at anti-aggregant doses), oral anti-diabetic drugs (except metformin), calcium-channel blockers, and diuretics at anti-edema doses are excluded from the study.
• Treatment with systemic corticosteroids within four weeks prior to enrolment and during the study was not allowed.
• Patients who have taken beta-blockers are to have been on a stable dose for four weeks before entry in the study.

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 40 Years

Maximum Age for this Clinical Trial: 80 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Takeda Global Research & Development Centre (Europe) Ltd.

Overall Clinical Trial Officials and Contacts

Medical Director Study Director Takeda Global Research & Development Centre (Europe) Ltd.  

Information obtained from ClinicalTrials.gov on July 02, 2009

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00676260

Study ID Number: AD4833/EC412

ClinicalTrials.gov Identifier: NCT00676260

Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency