Study In Postmenopausal Women With Type 2 Diabetes Looking At Approved Diabetes Drugs And How They Affect Bone Health

A 52 Week Randomized, Double-Blind, Multicenter, Mechanistic Study With a 24 Week Open-Label Follow-Up to Evaluate the Effect of AVANDIA TM on Bone in Postmenopausal Women With Type 2 Diabetes Mellitus

The purpose of this study is to determine the effects of rosiglitazone on the bone in postmenopausal women with type 2 diabetes mellitus

Study Overview

• Status: Completed
• Conditions: Diabetes Mellitus, Type 2
• Intervention / Treatment: Drug: Rosiglitazone; Drug: Metformin

• Study Type: Interventional
• Enrollment (Actual): 226
• Phase: Phase 4

Contacts and Locations

Study Locations

• Argentina
  • Buenos Aires, Argentina, 1425
    • GSK Investigational Site
  • Ciudad Autónoma de Buenos Aires, Argentina, C1128AAF
    • GSK Investigational Site
  • Buenos Aires
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, B1704ETD
      • GSK Investigational Site
    • Ciudad Autonoma de Buenos Aires, Buenos Aires, Argentina, C1012AAR
      • GSK Investigational Site
• Canada
  • British Columbia
    • Vancouver, British Columbia, Canada, V6H 3X8
      • GSK Investigational Site
  • Ontario
    • Brampton, Ontario, Canada, L6T 3T1
      • GSK Investigational Site
  • Quebec
    • Granby, Quebec, Canada, J2G 8Z9
      • GSK Investigational Site
• Estonia
  • Tallin, Estonia, 13419
    • GSK Investigational Site
  • Tallinn, Estonia, 13415
    • GSK Investigational Site
• Mexico
  • Durango, Mexico, 34000
    • GSK Investigational Site
  • Morelos
    • Cuernavaca, Morelos, Mexico, 62250
      • GSK Investigational Site
  • Nuevo León
    • Monterrey, Nuevo León, Mexico, 64460
      • GSK Investigational Site
  • Yucatán
    • Mérida, Yucatán, Mexico, 97129
      • GSK Investigational Site
• Pakistan
  • Lahore, Pakistan, 54000
    • GSK Investigational Site
• Philippines
  • Manila, Philippines, 01008
    • GSK Investigational Site
  • Marikina City, Philippines, 1810
    • GSK Investigational Site
• Spain
  • Alicante, Spain, 03114
    • GSK Investigational Site
  • Benidorm/Alicante, Spain, 03503
    • GSK Investigational Site
  • Granada, Spain, 18003
    • GSK Investigational Site
  • Granada, Spain, 18014
    • GSK Investigational Site
  • Petrer, Spain, 03610
    • GSK Investigational Site
• United States
  • Arizona
    • Tucson, Arizona, United States, 85745
      • GSK Investigational Site
  • California
    • Huntington Park, California, United States, 90255
      • GSK Investigational Site
    • Los Angeles, California, United States, 90022
      • GSK Investigational Site
    • Sacramento, California, United States, 95823
      • GSK Investigational Site
    • San Diego, California, United States, 92117
      • GSK Investigational Site
    • Torrance, California, United States, 90502
      • GSK Investigational Site
    • Vista, California, United States, 92081
      • GSK Investigational Site
  • Florida
    • Miami, Florida, United States, 33143
      • GSK Investigational Site
    • Miami, Florida, United States, 33156
      • GSK Investigational Site
  • Kentucky
    • Lexington, Kentucky, United States, 40504
      • GSK Investigational Site
  • Louisiana
    • Slidell, Louisiana, United States, 70461
      • GSK Investigational Site
  • Nevada
    • Las Vegas, Nevada, United States, 89117
      • GSK Investigational Site
  • New Mexico
    • Albuquerque, New Mexico, United States, 87106
      • GSK Investigational Site
    • Albuquerque, New Mexico, United States, 87102
      • GSK Investigational Site
  • New York
    • East Syracuse, New York, United States, 13057
      • GSK Investigational Site
    • Kingston, New York, United States, 12401
      • GSK Investigational Site
  • South Carolina
    • Columbia, South Carolina, United States, 29204
      • GSK Investigational Site
    • Columbia, South Carolina, United States, 29201
      • GSK Investigational Site
  • Tennessee
    • Kingsport, Tennessee, United States, 37660
      • GSK Investigational Site
  • Texas
    • San Antonio, Texas, United States, 78221
      • GSK Investigational Site
  • Washington
    • Wenatchee, Washington, United States, 98801
      • GSK Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 55 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

Description

Inclusion Criteria:

• Female, >55 to <80 years
• >5 years menopausal
• Type 2 Diabetes Mellitus (T2DM) diagnosis according to American Diabetes Association (ADA), American Association of Clinical Endocrinologists (AACE), Canadian Diabetes Association (CDA), World Health Organization/International Diabetes Federation (WHO/IDF)
• Drug-naïve (HbA1c < or = 9.0%); OR Prior monotherapy, submaximal doses of metformin (< or = 1000mg Metformin), sulfonylureas (< or = 5mg Glyburide, < or = 10mg Glipizide or < or = 8mg glimepiride) or full dose Januvia (100mg) (HbA1c < or = 8.5%); OR Prior monotherapy, > submaximal doses of metformin (>1000mg) or sulfonylureas (>5mg Glyburide, >10mg Glipizide or >8mg glimepiride) (HbA1c < or = 7.0%)
• Weighs <300 lbs (136.4 kg)
• Two or more vertebra (L1-L4) suitable for BMD measurement by dual x-ray absorptiometry (DXA)
• Absolute BMD value consistent with T-score >-2.5 at femoral neck, lumbar spine and total hip

Exclusion Criteria:

• Type 1 Diabetes Mellitus (T1DM) or history of diabetic ketoacidosis (DKA)
• Renal or hepatic disease (clinically significant)
• Hepatocellular reaction, severe edema, or medically serious fluid event associated with thiazolidinedione (TZD)
• Recent (<6mos) history or clinical intervention for angina or myocardial infarction or is taking nitrates
• Any stage of heart failure, i.e. New York Heart Association (NYHA) class I-IV
• Systolic BP >160mmHg or diastolic BP >90mmHg while on antihypertensive
• Hypersensitivity to TZDs, biguanides
• Prior treatment with two or more oral anti-diabetic (OAD) agents
• Bilateral hip replacements
• Concurrent diseases affecting bone metabolism
• Active malabsorption syndrome
• Serum calcium outside the central lab reference range
• Thyroid replacement therapy, serum thyroid stimulating hormone (TSH) must be within range
• Vitamin D deficiency
• Previous treatment with: strontium, intravenous (IV) bisphosphonate, fluoride, hormones, calcineurin inhibitors or methotrexate
• Chronic systemic corticosteroid [e.g. glucocorticoid, mineralocorticoid] treatment of no more than two intra-articular injections within the past year or use of oral parenteral, or long-term, high-dose inhaled corticosteroids

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Arm 1 Treatment A; rosiglitazone up to 8mg/day	Drug: Rosiglitazone; up to 8mg/day
Active Comparator: Arm 2 Treatment B; metformin up to 2000mg/day	Drug: Metformin; up to 2000mg/day

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Percent Change From Baseline in Femoral Neck (FN) Bone Mineral Density (BMD) Via Dual-energy X-ray Absorptiometry (DXA) at Week 52	FN BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Bone mineral density is calculated as the mineral content of a bone divided by the area of the bone. DXA is the principal technique used for measuring BMD. Percent change from Baseline at Week 52 was calculated as (BMD at Week 52 minus BMD at Baseline)/BMD at Baseline x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region. Change in FN BMD at Week 52 was only analyzed within the Rosiglitazone arm.	Baseline and Week 52
Adjusted Percent Change From Baseline in Femoral Neck (FN) Bone Mineral Density (BMD) Via Dual-energy X-ray Absorptiometry (DXA) at Week 76+10 Days	FN BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Bone mineral density is calculated as the mineral content of a bone divided by the area of the bone. DXA is the principal technique used for measuring BMD. Percent change from Baseline at Week 76+10 days was calculated as (BMD at Week 76+10 days minus BMD at Baseline)/BMD at Baseline x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region.	Baseline and Week 76+10 days
Adjusted Percent Change in Femoral Neck (FN) Bone Mineral Density (BMD) Via Dual-energy X-ray Absorptiometry (DXA) From Week 52 +10 Days to Week 76+10 Days	FN BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Bone mineral density is calculated as the mineral content of a bone divided by the area of the bone. DXA is the principal technique used for measuring BMD. Percent change from Week 52+10 days to Week 76+10 days was calculated as (BMD at Week 76+10 days minus BMD at Week 52+10 days)/BMD at Week 52+10 days x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region.	Week 52+10 days and Week 76+10 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adjusted Percent Change From Baseline in Femoral Neck, Total Hip, Trochanter, and Lumbar Spine BMD Via DXA at Week 52	BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Percent change from Baseline at Week 52 was calculated as (BMD at Week 52 minus BMD at Baseline)/BMD at Baseline x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region.	Baseline and Week 52
Adjusted Percent Change in Femoral Neck, Total Hip, Trochanter, and Lumbar Spine BMD Via DXA From Week 52+10 Days to Week 76 + 10 Days	BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Percent change from Week 52 + 10 days toat Week 76 + 10 days was calculated as (BMD at Week 76 + 10 days minus BMD at Week 52 + 10 days)/BMD at Week 52 + 10 days x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region.	Week 52 + 10 days and Week 76 + 10 days
Adjusted Percent Change in Femoral Neck, Total Hip, Trochanter, and Lumbar Spine BMD Via DXA From Week 52+30 Days to Week 76 + 30 Days	BMD (measured in grams per centimeters squared [g/cm^2]) was measured by DXA. Percent change from Week 52 + 30 days to Week 76 + 30 days was calculated as (BMD at Week 76 + 30 days minus BMD at Week 52 + 30 days)/BMD at Week 52 + 30 days x 100% and was assessed by analysis of covariance (ANCOVA) with terms for treatment, baseline value, prior therapy, and region.	Week 52 + 30 days and Week 76 + 30 days
Adjusted Percent Change From Baseline in Bone Specific Alkaline Phosphatase (BSAP) and Procollagen Type 1 N-propeptide (P1NP) at Week 52 and Week 76	BSAP and P1NP levels were measured in micrograms per liter (mcg/L) from blood samples. BSAP and P1NP are indicators of bone buildup or formation. GM, geometric mean; SE, standard error. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Baseline, Week 52, and Week 76
Adjusted Percent Change in Bone Specific Alkaline Phosphatase (BSAP) and Procollagen Type 1 N-propeptide (P1NP) From Week 52 to Week 76	BSAP and P1NP levels were measured in micrograms per liter (mcg/L) from blood samples. BSAP and P1NP are indicators of bone buildup or formation. GM, geometric mean; SE, standard error. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Week 52 and Week 76
Adjusted Percent Change From Baseline in Carboxyterminal Cross-linked Telopeptide of Type 1 Collagen (CTX) at Week 52 and Week 76	CTX levels were measured in picograms per milliliter (pg/ml) from blood samples. CTX is an indicator of bone break down or resorption. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Baseline, Week 52, and Week 76
Adjusted Percent Change in Carboxyterminal Cross-linked Telopeptide of Type 1 Collagen (CTX) From Week 52 to Week 76	CTX levels were measured in picograms per milliliter (pg/ml) from blood samples. CTX is an indicator of bone break down or resorption. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Week 52 and Week 76
Adjusted Percent Change From Baseline in 25-Hydroxyvitamin D (Vitamin D) at Week 52 and Week 76	Vitamin D levels were measured in nanomoles per Liter (nmol/L) from blood samples. Vitamin D is required for good bone health. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Baseline, Week 52, and Week 76
Adjusted Percent Change in 25-Hydroxyvitamin D (Vitamin D) From Week 52 to Week 76	Vitamin D levels were measured in nanomoles per Liter (nmol/L) from blood samples. Vitamin D is required for good bone health. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Week 52 and Week 76
Adjusted Percent Change From Baseline in Intact Parathyroid Hormone (PTH) at Week 52 and Week 76	Intact PTH levels were measured in nanograms per Liter (ng/L) from blood samples. Intact PTH is the amount of PTH circulating in the blood and influences bone health. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Baseline, Week 52, and Week 76
Adjusted Percent Change in Intact Parathyroid Hormone (PTH) From Week 52 to Week 76	Intact PTH levels were measured in nanograms per Liter (ng/L) from blood samples. Intact PTH is the amount of PTH circulating in the blood and influences bone health. Percent change was based on log-transformed data and was assessed by an ANCOVA with terms for treatment, baseline value, prior therapy, and region.	Week 52 and Week 76
Percent Change From Baseline in Serum Estradiol at Week 52 and Week 76	Serum estradiol levels were measured in picomoles per Liter (pmol/L) from blood samples. Estradiol is one form of the female sex hormone estrogen and influences bone health. Percent change from baseline was based on log-transformed data.	Baseline, Week 52, and Week 76
Percent Change in Serum Estradiol From Week 52 to Week 76	Serum estradiol levels were measured in picomoles per Liter (pmol/L) from blood samples. Estradiol is one form of the female sex hormone estrogen and influences bone health. Percent change from baseline was based on log-transformed data.	Week 52 and Week 76
Percent Change From Baseline in Total Testosterone at Week 52 and Week 76	Total testosterone levels were measured in nanomoles per Liter (nmol/L) from blood samples. Testosterone is a male sex hormone and influences bone health; total testosterone is the entire amount circulating in blood. Percent change from baseline was based on log-transformed data.	Baseline, Week 52, and Week 76
Percent Change in Total Testosterone From Week 52 to Week 76	Total testosterone levels were measured in nanomoles per Liter (nmol/L) from blood samples. Testosterone is a male sex hormone and influences bone health; total testosterone is the entire amount circulating in blood. Percent change from baseline was based on log-transformed data.	Week 52 and Week 76
Percent Change From Baseline in Free Testosterone at Week 52 and Week 76	Free testosterone levels were measured as a percentage of total testosterone from blood samples. Free testosterone is the amount of testosterone available to the body for use. Percent change from baseline was based on log-transformed data.	Baseline, Week 52, and Week 76
Percent Change in Free Testosterone From Week 52 to Week 76	Free testosterone levels were measured as a percentage of total testosterone from blood samples. Free testosterone is the amount of testosterone available to the body for use. Percent change from baseline was based on log-transformed data.	Week 52 and Week 76
Percent Change From Baseline in Sex Hormone Binding Globulin (SHBG) at Week 52 and Week 76	SHBG levels were measured in nanomoles per liter (nmol/L) from blood samples. SHBG binds to estradiol and testosterone and influences the amount of estradiol or testosterone available to the body for use. Percent change from baseline was based on log-transformed data.	Baseline, Week 52, and Week 76
Percent Change in Sex Hormone Binding Globulin (SHBG) From Week 52 to Week 76	SHBG levels were measured in nanomoles per liter (nmol/L) from blood samples. SHBG binds to estradiol and testosterone and influences the amount of estradiol or testosterone available to the body for use. Percent change from baseline was based on log-transformed data.	Week 52 and Week 76

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Percent Change in Percentage of Free Estradiol From Week 52 to Week 76	Free estradiol levels were measured as a percentage of serum estrogen from blood samples. Free estradiol is the amount of estrogen available to the body for use. Percent change was based on log-transformed data.	Week 52 and Week 76
Percent Change in Free Estradiol From Week 52 to Week 76	Free estradiol levels were measured in picomoles per Liter (pmol/L) from blood samples. Free estrodial is the amount of estrogen available to the body for use. Change was based on log-transformed data.	Week 52 and Week 76

Collaborators and Investigators

• Sponsor: GlaxoSmithKline

Publications and helpful links

General Publications

• Fitzpatrick LA, Bilezikian JP, Wooddell M, Paul G, Kolatkar NS, Nino AJ, Miller CG, Bogado CE, Arnaud CD, Cobitz AR. Mechanism of action study to evaluate the effect of rosiglitazone on bone in postmenopausal women with type 2 diabetes mellitus: rationale, study design and baseline characteristics. J Drug Assess. 2011 Dec 16;1(1):11-9. doi: 10.3109/21556660.2011.641703. eCollection 2012.
• Gnesin F, Thuesen ACB, Kahler LKA, Madsbad S, Hemmingsen B. Metformin monotherapy for adults with type 2 diabetes mellitus. Cochrane Database Syst Rev. 2020 Jun 5;6(6):CD012906. doi: 10.1002/14651858.CD012906.pub2.
• Miller CG, Bogado CC, Nino AJ, Northcutt AR, Yu HJ, Lewiecki EM, Paul G, Cobitz AR, Wooddell MJ, Bilezikian JP, Fitzpatrick LA. Evaluation of Quantitative Computed Tomography Cortical Hip Quadrant in a Clinical Trial With Rosiglitazone: A Potential New Study Endpoint. J Clin Densitom. 2016 Oct;19(4):485-491. doi: 10.1016/j.jocd.2016.02.003. Epub 2016 Mar 24.
• Bilezikian JP, Josse RG, Eastell R, Lewiecki EM, Miller CG, Wooddell M, Northcutt AR, Kravitz BG, Paul G, Cobitz AR, Nino AJ, Fitzpatrick LA. Rosiglitazone decreases bone mineral density and increases bone turnover in postmenopausal women with type 2 diabetes mellitus. J Clin Endocrinol Metab. 2013 Apr;98(4):1519-28. doi: 10.1210/jc.2012-4018. Epub 2013 Feb 28.

Helpful Links

• Researchers can use this site to request access to anonymised patient level data and/or supporting documents from clinical studies to conduct further research.

Study record dates

Study Major Dates

• Study Start: April 21, 2008
• Primary Completion (Actual): September 16, 2010
• Study Completion (Actual): September 16, 2010

Study Registration Dates

• First Submitted: May 15, 2008
• First Submitted That Met QC Criteria: May 15, 2008
• First Posted (Estimate): May 19, 2008

Study Record Updates

• Last Update Posted (Actual): April 18, 2018
• Last Update Submitted That Met QC Criteria: March 19, 2018
• Last Verified: March 1, 2018

More Information

Terms related to this study

• Keywords: Type 2 diabetes mellitus; bone; x-ray absorptiometry; bone biomarkers; dual-energy; bone mineral density
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Diabetes Mellitus; Diabetes Mellitus, Type 2; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin; Rosiglitazone
• Other Study ID Numbers: AVD111179

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: Patient-level data for this study will be made available through www.clinicalstudydatarequest.com following the timelines and process described on this site.

Study Data/Documents

1. Annotated Case Report Form
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
2. Informed Consent Form
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
3. Study Protocol
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
4. Individual Participant Data Set
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
5. Dataset Specification
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
6. Clinical Study Report
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register
7. Statistical Analysis Plan
   Information identifier: AVD111179
   Information comments: For additional information about this study please refer to the GSK Clinical Study Register

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No