Clinical trial NCT00386100: A Type 2 Diabetes Study of the Longer-Term Glycemic Effect of AVANDAMET vs. Metformin
Official title: A Randomized, Parallel Group, Double-blind, Multi-center Study Comparing the Efficacy and Safety of AVANDAMET and Metformin After 80 Weeks of Treatment.
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE4
Conditions: Diabetes Mellitus, Type 2
Keywords: Fasting Plasma Glucose
Dual energy X ray absorptiometry (DXA)
Drug-naive
Type 2 diabetes mellitus
Bone Mineral Density
Hyperglycemia
HbA1c
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2006-10-11
Enrollment: 688
Sex: ALL
Minimum age (years): 18
Maximum age (years): 75
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This study will evaluate the longer-term glycemic effect of two medicines approved for initial treatment of type 2 diabetes. The study consists of a 2 week screening period (2 study visits), followed by an 80 week double-blind treatment period (11 study visits). Also, a sub-study was included to look at changes in bone mineral density (BMD) at the lumbar spine.

Detailed description: This was a phase IV, randomized, double-blind, global, multi-centre study. The study consisted of a 2 week screening period followed by an 80 week double-blind treatment period. Subjects who met all eligibility requirements were randomized in a 1:1 ratio, stratified by country, gender (male and female) and pre-screening HbA1c (≤9% or\>9) either to MET or AVM. When the substudy was added, a new randomization was created for the participating centers. Those subjects in the bone sub-study were stratified by country, gender (male, premenopausal female, and postmenopausal female), pre-screening HbA1c (i.e., ≤9%; \>9%), and either to MET or AVM.

At randomization, Visit 3 (Week 0), subjects were initiated at Dose Level 1. Treatment with AVM was initiated at a dose of 4 mg/500 mg and titrated up to a maximum total daily dose of AVM 8 mg/2000 mg. Treatment with MET therapy was initiated at a dose of 500 mg and titrated up to a maximum daily dose of 2000mg.

Eligibility criteria: Inclusion Criteria:

* The subject provides written informed consent.
* The subject is male or female and 18 to 75 years of age at the time of pre-screening.
* The subject has an established clinical diagnosis of type 2 diabetes according to recommended guidelines (e.g., American Diabetes Association, International Diabetes Federation, World Health Organization, Canadian Diabetes Association, or American Association of Clinical Endocrinologists).
* The subject is currently treated with diet and exercise, and has not taken more than 2 weeks of an anti-diabetic monotherapy or insulin in the past 6 months.
* The subject has a BMI \>25 kg/m2 at pre-screening.
* The subject has a Quest HbA1c 7.5% to 10.5% at pre-screening.
* The subject has a fasting capillary blood glucose 126 mg/dL (7mmol/L), as measured by the site staff at week 0.
* If the subject is a pre-menopausal female of child-bearing potential, she agrees to practice acceptable contraceptive measures (e.g. oral birth control pills, Norplant, Depo-Provera, an intrauterine device (IUD), a diaphragm with spermicide or a condom with spermicide, or abstinence) at least 1 month before screening, during the study, and for 30 days after the last dose of study medication is taken
* The subject is able and willing to perform self-monitoring of blood glucose as specified in this protocol.

Exclusion Criteria:

* The subject has taken an oral anti-diabetic monotherapy or insulin for more than 14 days in the past 6 months.
* The subject has presence of clinically significant renal or hepatic disease (serum creatinine 1.5 mg/dL (132.6 mol/L) for males and 1.4 mg/dL (123.8 mol/L) for females): ALT, AST, total bilirubin, or alkaline phosphatase \>2.5 times the upper limit of the normal (ULN) reference range.
* The subject has anemia defined by hemoglobin concentration \<11g/dL (110g/L) for males or \<10g/dL (100g/L) for females.
* Presence of unstable or severe angina, coronary insufficiency or New York Heart Association (NYHA) class III-IV or any congestive heart failure requiring pharmacologic treatment.
* The subject has systolic blood pressure \>160 mmHg or diastolic blood pressure \>90 mmHg
* The subject has a chronic disease requiring intermittent or chronic treatment with oral, intravenous, or intra-articular corticosteroids (i.e., only use of topical, inhaled or nasal corticosteroids is permitted).
* The subject has acute or chronic metabolic acidosis or a history of diabetic ketoacidosis.
* The subject has a clinically significant abnormality which in the judgment of the investigator makes the subject unsuitable for inclusion in the study (e.g., physical examination, laboratory tests, or electrocardiogram, etc).
* The subject has used an investigational agent within 30 days or 5 half-lives (whichever was longer) prior to pre-screening.
* The subject is a female who is lactating, pregnant, or planned to become pregnant.
* The subject has a prior history of severe edema or a medically serious fluid related event (e.g., heart failure).
* The subject has a history of macular edema.
* The subject has significant hypersensitivity (e.g., difficulty swallowing, difficulty breathing, and tachycardia or skin reaction) to TZDs, biguanides, or compounds with similar chemical structures.
* The subject has a diagnosis of cancer (other than squamous, basal cell, or cervical cancer in-situ) in the past 3 years and is receiving treatment for cancer.
* The subject has a history or suspicion of drug abuse or alcohol abuse within the last 6 months.
* The subject is known to have severe lactose intolerance.
* The subject is not willing to comply with visits and procedures described in the protocol.
* The subject has a disease that may affect bone turnover including, but not limited to: Paget's disease, hypercalcemia, hypocalcemia, hyperparathyroidism, hyperthyroidism, osteomalacia, metastatic bone disease
* The subject has a weight of greater than 300 lbs (136.4 kg).
* The subject has received treatment with bisphosphonates (≥1 month cumulative treatment within the last 12 months) or fluoride (dose greater than 10mg/day within the previous 5 years).

Primary outcomes:
measure: Change From Baseline in HbA1c at Week 80
timeFrame: Baseline and Week 80
Secondary outcomes:
measure: Mean Change From Baseline in HbA1c at Week 80
timeFrame: Baseline and Week 80
measure: Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80
timeFrame: Week 80
measure: Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80
timeFrame: Baseline and Week 80
measure: Change From Baseline in FPG at Week 80
timeFrame: Baseline and Week 80
measure: Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80
timeFrame: Week 80
measure: Number of Participants Achieving Treatment Failure
timeFrame: Randomization to treatment failure (up to Week 80)
measure: Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80
timeFrame: Baseline and Week 80
measure: Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )
timeFrame: Baseline and Week 80
measure: Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)
timeFrame: Baseline and Week 80
measure: Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).
timeFrame: Baseline and Week 80
measure: Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)
timeFrame: Baseline and Week 80
measure: Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)
timeFrame: Baseline and Week 80
measure: Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)
timeFrame: Baseline and Week 80
measure: Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG
timeFrame: Baseline and Week 80
measure: Number of Participants at Final Dose Level
timeFrame: Baseline to Week 80 or withdrawal
measure: Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80
timeFrame: Baseline and Weeks 12, 32, 56, and 80
measure: Percent Change From Baseline in Intact Parathyroid Hormone at Week 80
timeFrame: Baseline and Week 80
measure: Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80
timeFrame: Baseline and Week 80
measure: Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80
timeFrame: Baseline and Weeks 20, 56, and 80
measure: Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80
timeFrame: Baseline and Weeks 20, 56, and 80
Other outcomes:
Locations:
city: Tuscaloosa
country: United States
facility: GSK Investigational Site
state: Alabama
city: Gilbert
country: United States
facility: GSK Investigational Site
state: Arizona
city: Glendale
country: United States
facility: GSK Investigational Site
state: Arizona
city: Phoenix
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Tucson
country: United States
facility: GSK Investigational Site
state: Arizona
city: Alhambra
country: United States
facility: GSK Investigational Site
state: California
city: Artesia
country: United States
facility: GSK Investigational Site
state: California
city: Greenbrae
country: United States
facility: GSK Investigational Site
state: California
city: Roseville
country: United States
facility: GSK Investigational Site
state: California
city: Sacramento
country: United States
facility: GSK Investigational Site
state: California
city: Wheat Ridge
country: United States
facility: GSK Investigational Site
state: Colorado
city: Hialeah
country: United States
facility: GSK Investigational Site
state: Florida
city: Ocala
country: United States
facility: GSK Investigational Site
state: Florida
city: Kahului
country: United States
facility: GSK Investigational Site
state: Hawaii
city: Peoria
country: United States
facility: GSK Investigational Site
state: Illinois
city: Avon
country: United States
facility: GSK Investigational Site
state: Indiana
city: Evansville
country: United States
facility: GSK Investigational Site
state: Indiana
city: Evansville
country: United States
facility: GSK Investigational Site
state: Indiana
city: Indianapolis
country: United States
facility: GSK Investigational Site
state: Indiana
city: Waterloo
country: United States
facility: GSK Investigational Site
state: Iowa
city: Slidell
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Sunset
country: United States
facility: GSK Investigational Site
state: Louisiana
city: Elkridge
country: United States
facility: GSK Investigational Site
state: Maryland
city: Chaska
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Minneapolis
country: United States
facility: GSK Investigational Site
state: Minnesota
city: Excelsior Springs
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Louis
country: United States
facility: GSK Investigational Site
state: Missouri
city: St. Peters
country: United States
facility: GSK Investigational Site
state: Missouri
city: Billings
country: United States
facility: GSK Investigational Site
state: Montana
city: Las Vegas
country: United States
facility: GSK Investigational Site
state: Nevada
city: Pahrump
country: United States
facility: GSK Investigational Site
state: Nevada
city: Hamilton
country: United States
facility: GSK Investigational Site
state: New Jersey
city: Albuquerque
country: United States
facility: GSK Investigational Site
state: New Mexico
city: East Syracuse
country: United States
facility: GSK Investigational Site
state: New York
city: Flushing
country: United States
facility: GSK Investigational Site
state: New York
city: Kingston
country: United States
facility: GSK Investigational Site
state: New York
city: Huntersville
country: United States
facility: GSK Investigational Site
state: North Carolina
city: Canal Fulton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Canton
country: United States
facility: GSK Investigational Site
state: Ohio
city: Cleveland
country: United States
facility: GSK Investigational Site
state: Ohio
city: Columbus
country: United States
facility: GSK Investigational Site
state: Ohio
city: Kettering
country: United States
facility: GSK Investigational Site
state: Ohio
city: Mogadore
country: United States
facility: GSK Investigational Site
state: Ohio
city: Wandsworth
country: United States
facility: GSK Investigational Site
state: Ohio
city: Oregon City
country: United States
facility: GSK Investigational Site
state: Oregon
city: Beaver
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Clairton
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Coatsville
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Erie
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Sewickley
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: West Chester
country: United States
facility: GSK Investigational Site
state: Pennsylvania
city: Clinton
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Columbia
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Pelzer
country: United States
facility: GSK Investigational Site
state: South Carolina
city: Kingsport
country: United States
facility: GSK Investigational Site
state: Tennessee
city: Corpus Christi
country: United States
facility: GSK Investigational Site
state: Texas
city: Dallas
country: United States
facility: GSK Investigational Site
state: Texas
city: Georgetown
country: United States
facility: GSK Investigational Site
state: Texas
city: South Burlington
country: United States
facility: GSK Investigational Site
state: Vermont
city: Burke
country: United States
facility: GSK Investigational Site
state: Virginia
city: Manassas
country: United States
facility: GSK Investigational Site
state: Virginia
city: Salem
country: United States
facility: GSK Investigational Site
state: Virginia
city: Gig Harbor
country: United States
facility: GSK Investigational Site
state: Washington
city: Graham
country: United States
facility: GSK Investigational Site
state: Washington
city: Olympia
country: United States
facility: GSK Investigational Site
state: Washington
city: Tacoma
country: United States
facility: GSK Investigational Site
state: Washington
city: Vancouver
country: United States
facility: GSK Investigational Site
state: Washington
city: Wenatchee
country: United States
facility: GSK Investigational Site
state: Washington
city: Wauwatosa
country: United States
facility: GSK Investigational Site
state: Wisconsin
city: Buenos Aries
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Capital Federal
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Ciudad Autonoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
state: Buenos Aires
city: Cordoba
country: Argentina
facility: GSK Investigational Site
state: Córdova
city: Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Ciudad Autónoma de Buenos Aires
country: Argentina
facility: GSK Investigational Site
city: Mendoza
country: Argentina
facility: GSK Investigational Site
city: Fortaleza
country: Brazil
facility: GSK Investigational Site
state: Ceará
city: Goiânia
country: Brazil
facility: GSK Investigational Site
state: Goiás
city: Porto Alegre
country: Brazil
facility: GSK Investigational Site
state: Rio Grande Do Sul
city: Campinas
country: Brazil
facility: GSK Investigational Site
state: São Paulo
city: Brasília
country: Brazil
facility: GSK Investigational Site
city: São Paulo
country: Brazil
facility: GSK Investigational Site
city: Coquitlam
country: Canada
facility: GSK Investigational Site
state: British Columbia
city: Bathurst
country: Canada
facility: GSK Investigational Site
state: New Brunswick
city: Bay Roberts
country: Canada
facility: GSK Investigational Site
state: Newfoundland and Labrador
city: St. John's
country: Canada
facility: GSK Investigational Site
state: Newfoundland and Labrador
city: Brampton
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Smiths Falls
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Toronto
country: Canada
facility: GSK Investigational Site
state: Ontario
city: Gatineau
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Sherbrooke
country: Canada
facility: GSK Investigational Site
state: Quebec
city: Gwangju
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Seoul
country: Korea, Republic of
facility: GSK Investigational Site
city: Suwon, Kyonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Uijeongbu-si, Kyonggi-do
country: Korea, Republic of
facility: GSK Investigational Site
city: Tijuana
country: Mexico
facility: GSK Investigational Site
state: Baja California Norte
city: Pachuca
country: Mexico
facility: GSK Investigational Site
state: Hidalgo
city: Monterrey
country: Mexico
facility: GSK Investigational Site
state: Nuevo León
city: Durango
country: Mexico
facility: GSK Investigational Site
city: Karachi
country: Pakistan
facility: GSK Investigational Site
city: Lahore
country: Pakistan
facility: GSK Investigational Site
city: Cebu City
country: Philippines
facility: GSK Investigational Site
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Manila
country: Philippines
facility: GSK Investigational Site
city: Marikina City
country: Philippines
facility: GSK Investigational Site
city: Quezon City
country: Philippines
facility: GSK Investigational Site
city: Changhua
country: Taiwan
facility: GSK Investigational Site
city: Kaohsiung
country: Taiwan
facility: GSK Investigational Site
city: Taichung
country: Taiwan
facility: GSK Investigational Site
city: Taipei
country: Taiwan
facility: GSK Investigational Site
city: Taoyuan Hsien
country: Taiwan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Borges JL, Bilezikian JP, Jones-Leone AR, Acusta AP, Ambery PD, Nino AJ, Grosse M, Fitzpatrick LA, Cobitz AR. A randomized, parallel group, double-blind, multicentre study comparing the efficacy and safety of Avandamet (rosiglitazone/metformin) and metformin on long-term glycaemic control and bone mineral density after 80 weeks of treatment in drug-naive type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011 Nov;13(11):1036-46. doi: 10.1111/j.1463-1326.2011.01461.x.