Clinical trial NCT00708175: Efficacy of Pioglitazone on Bone Metabolism in Postmenopausal Women With Impaired Fasting Glucose.
Official title: A Phase 4, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Effect of Pioglitazone Compared to Placebo on Bone Metabolism in Impaired Fasting Glucose, Postmenopausal Women for One Year of Treatment
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Bone Metabolism
Keywords: Glucose Metabolism Disorder
Dysmetabolic Syndrome
Type II Diabetes
Diabetes Mellitus
Lipoatrophic
Postmenopausal
Lead sponsor: Takeda
Sponsor class: INDUSTRY
First posted: 2008-07-02
Enrollment: 156
Sex: FEMALE
Maximum age (years): 70
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to evaluate the effect of pioglitazone on bone metabolism in postmenopausal women with impaired fasting glucose.

Detailed description: The World Health Organization has estimated that 30% of all women aged over 50 years (postmenopausal) have osteoporosis according to a definition of Bone Mineral Density at any site being more than 2.5 standard deviations below the mean for young healthy adult women.

A known risk factor for development of osteoporosis and fracture is diabetes mellitus, with correlations to duration of disease and poor glycemic control.

Pioglitazone is a thiazolidinedione developed by Takeda Pharmaceuticals for the treatment of type 2 diabetes. Preclinical studies to date on the bone effects of thiazolidinediones have not clearly identified a mechanism of bone loss. While there is evidence of increased bone fractures in postmenopausal diabetic females treated with a thiazolidinedione, the mechanism is not known. Initial studies with thiazolidinediones in humans have focused on short term exposure (12 to 14 weeks) and non-diabetic females. These studies have shown acute changes in circulating bone markers and bone density, but have been questioned because they may not represent bone metabolism in states of abnormal glucose metabolism. Impaired glucose tolerance has been identified not only as a risk factor for developing type 2 diabetes, but also at higher risk for known complications of diabetes. Examination of the effect of thiazolidinediones on bone metabolism in IGT patients will provide data in patients with abnormal glucose tolerance, but without the potential confounding effects of oral hypoglycemic medications to treat type 2 diabetes.

The primary objective of this study is to evaluate the effect of pioglitazone on bone mass and metabolism in postmenopausal women with impaired fasting glucose or impaired glucose tolerance. Total participation time in this study is approximately 1 year and six months.

Eligibility criteria: Inclusion Criteria:

* Is female and has not experienced menses for at least 5 years.
* Has a Fasting Plasma Glucose level greater than or equal to 100 and less than 126 mg/dL or a 2-hour post-oral glucose tolerance test greater than or equal to 140 and less than or equal to 199 mg/dL at Screening.
* Has a body mass index greater than or equal to 16 and less than or equal to 40 kg/m2 and weighs less than 300 pounds (approximately 136 kilograms).
* Agrees to take daily supplements of Vitamin D (a minimum of 800 IU daily) and calcium (a minimum of 1000 mg daily) during the treatment and wash-out periods.
* Has clinical laboratory evaluations (including clinical chemistry, hematology, and complete urinalysis \[fasted for at least 8 hours\]) within the reference range for the testing laboratory unless the results are deemed not clinically significant by the investigator or sponsor.
* Is in good health as determined by the physician (ie, via medical history and physical examination) at Screening.

Exclusion Criteria:

* Has a fasting triglyceride level greater than 500 mg/dL.
* Has a hemoglobinopathy causing anemia or interfering with glycosylated hemoglobin assays.
* Has an alanine transaminase level greater than or equal to 2.5 times the upper limit of normal, active liver disease or jaundice.
* Has Vitamin D (25-OH-D) less than 20 ng/mL.
* Has Baseline Bone Mineral Density defined as a T-score less than -2.0 at the total hip, spine, or femoral neck based on Caucasian reference values.
* Has unexplained microscopic or macroscopic hematuria confirmed by repeat testing.
* Has any of the following disorders:

  * Rheumatoid Arthritis
  * Thyroid (uncontrolled on thyroid replacement therapy), parathyroid, pituitary, nutritional, inflammatory, gastrointestinal, autoimmune, or renal or other disease known to affect bone metabolism.
  * A personal history of kidney stones.
* Has a clinical history after age 45 of wrist, hip, or leg fractures.
* Has a history of more than 1 asymptomatic vertebral deformity or any vertebral deformity attributed to osteoporosis.
* Has a known history of drug abuse (defined as illicit drug use) or a known history of alcohol abuse within 2 years of Screening.
* Has signs and/or symptoms of heart failure.
* Is currently participating in another investigational study or has participated in an investigational study within the past 30 days or 5 half lives of the investigational product, whichever is longer.
* Has any other serious disease or condition at screening or at randomization that might make it difficult to successfully manage and follow up with the subject according to the protocol.
* Has a history of cancer, other than basal cell carcinoma or Stage 1 squamous cell carcinoma of the skin that has not been in remission for at least 5 years prior to the first dose of study drug.
* Has a history of breast cancer.
* Is taking or has ever taken pioglitazone or other Thiazolidinediones.
* Has received or donated blood or blood products within 30 days preceding the Screening visit or plans to donate blood during the study.

Primary outcomes:
measure: Percent Change From Baseline to Month 12 in Bone Mineral Density in the Total Proximal Femur by Dual-Energy-Ray Absorptiometry (DXA)
timeFrame: Baseline and Month 12.
Secondary outcomes:
measure: Percent Change From Month 12 to Month 18 in Bone Mineral Density in the Total Proximal Femur by DXA
timeFrame: Month 12 and Month 18.
Other outcomes:
measure: Change in Fasting Plasma Glucose (FPG)
timeFrame: Baseline and Month 12; Month 12 and Month 18.
measure: Number of Participants Who Converted to Type 2 Diabetes Mellitus (T2DM)
timeFrame: Up to 18 months.
measure: Number of Participants With Fracture
timeFrame: Up to 18 months.
Locations:
city: Greenbrae
country: United States
state: California
city: Los Banos
country: United States
state: California
city: San Diego
country: United States
state: California
city: Walnut Creek
country: United States
state: California
city: West Hills
country: United States
state: California
city: Lakewood
country: United States
state: Colorado
city: Longmont
country: United States
state: Colorado
city: Boynton Beach
country: United States
state: Florida
city: Hialeah
country: United States
state: Florida
city: Jupiter
country: United States
state: Florida
city: Dunwoody,
country: United States
state: Georgia
city: Gainesville
country: United States
state: Georgia
city: Honolulu
country: United States
state: Hawaii
city: Idaho Falls
country: United States
state: Idaho
city: Chicago
country: United States
state: Illinois
city: Des Moines
country: United States
state: Iowa
city: Iowa City
country: United States
state: Iowa
city: Louisville
country: United States
state: Kentucky
city: Metarie
country: United States
state: Louisiana
city: Scarborough
country: United States
state: Maine
city: Bethesda
country: United States
state: Maryland
city: Detroit
country: United States
state: Michigan
city: Omaha
country: United States
state: Nebraska
city: Albuquerque
country: United States
state: New Mexico
city: Mineola
country: United States
state: New York
city: West Haverstraw
country: United States
state: New York
city: Pinehurst
country: United States
state: North Carolina
city: Cincinnati
country: United States
state: Ohio
city: Portland
country: United States
state: Oregon
city: Aiken
country: United States
state: South Carolina
city: Greenville
country: United States
state: South Carolina
city: Brentwood
country: United States
state: Tennessee
city: Denton
country: United States
state: Texas
city: Houston
country: United States
state: Texas
Study officials:
affiliation: Takeda
name: VP Clinical Science Strategy
role: STUDY_DIRECTOR
References:
citation: Ipsen EO, Madsen KS, Chi Y, Pedersen-Bjergaard U, Richter B, Metzendorf MI, Hemmingsen B. Pioglitazone for prevention or delay of type 2 diabetes mellitus and its associated complications in people at risk for the development of type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Nov 19;11(11):CD013516. doi: 10.1002/14651858.CD013516.pub2.
citation: Bone HG, Lindsay R, McClung MR, Perez AT, Raanan MG, Spanheimer RG. Effects of pioglitazone on bone in postmenopausal women with impaired fasting glucose or impaired glucose tolerance: a randomized, double-blind, placebo-controlled study. J Clin Endocrinol Metab. 2013 Dec;98(12):4691-701. doi: 10.1210/jc.2012-4096. Epub 2013 Sep 20.