A Type 2 Diabetes Study of the Longer-Term Glycemic Effect of AVANDAMET vs. Metformin

Diabetes Mellitus, Type 2 Clinical Trial

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.

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00386100
• Other study ID #: AVT105913
• Status: Completed
• Phase: Phase 4
• First received: October 9, 2006
• Last updated: June 17, 2015
• Start date: October 2006
• Est. completion date: September 2009

Study information

• Verified date: July 2013
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: Institutional Review BoardArgentina: Ministry of Health - A.N.M.A.TTaiwan: Department of HealthPhilippines: Bureau of Food and DrugsCanada: Health CanadaKorea: Korea Food & Drug AdministrationMexico: Ministry of HealthUnited States: Institutional Review BoardUnited States: Food and Drug Administration
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 688
• Est. completion date: September 2009
• Est. primary completion date: September 2009
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years to 75 Years

Eligibility

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).

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetes Mellitus
• Diabetes Mellitus, Type 2

Intervention

Drug:
• Avandamet 6 mg/1500 mg (ttd)
One 2 mg/ 500 mg capsule will be taken in the AM with the morning meal Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal
• Avandamet 4 mg/1000 mg (ttd)
One 2 mg/500 mg capsule will be taken in the AM with the morning meal. One 2 mg/500 mg capsule will be taken in the PM with the evening meal.
• Avandamet 2 mg/500 mg (ttd)
one placebo capsule will be taken in the AM with the morning meal one 2 mg/ 500 mg capsule will be taken in the PM with the evening meal.
• Avandamet 8 mg/ 2000 mg (ttd)
Two 2 mg/ 500 mg capsules will be taken in the AM with the morning meal. Two 2 mg/ 500 mg capsules will be taken in the PM with the evening meal.
• Metformin 500 mg (ttd)
One placebo capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.
• Metformin 1000 mg (ttd)
One 500 mg capsule will be taken in the AM with the morning meal. One 500 mg capsule will be taken in the PM with the evening meal.
• Metformin 1500 mg (ttd)
One 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsules will be taken in the PM with the evening meal.
• Metformin 2000 mg (ttd)
Two 500 mg capsule will be taken in the AM with the morning meal. Two 500 mg capsule will be taken in the PM with the evening meal.

Locations

Country	Name	City	State
Argentina	GSK Investigational Site	Buenos Aires
Argentina	GSK Investigational Site	Buenos Aries	Buenos Aires
Argentina	GSK Investigational Site	Capital Federal	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autonoma de Buenos Aires	Buenos Aires
Argentina	GSK Investigational Site	Ciudad Autónoma de Buenos Aires
Argentina	GSK Investigational Site	Cordoba	Córdova
Argentina	GSK Investigational Site	Mendoza
Brazil	GSK Investigational Site	Brasília
Brazil	GSK Investigational Site	Campinas	São Paulo
Brazil	GSK Investigational Site	Fortaleza	Ceará
Brazil	GSK Investigational Site	Goiânia	Goiás
Brazil	GSK Investigational Site	Porto Alegre	Rio Grande Do Sul
Brazil	GSK Investigational Site	São Paulo
Canada	GSK Investigational Site	Bathurst	New Brunswick
Canada	GSK Investigational Site	Bay Roberts	Newfoundland and Labrador
Canada	GSK Investigational Site	Brampton	Ontario
Canada	GSK Investigational Site	Coquitlam	British Columbia
Canada	GSK Investigational Site	Gatineau	Quebec
Canada	GSK Investigational Site	Sherbrooke	Quebec
Canada	GSK Investigational Site	Smiths Falls	Ontario
Canada	GSK Investigational Site	St. John's	Newfoundland and Labrador
Canada	GSK Investigational Site	Toronto	Ontario
Korea, Republic of	GSK Investigational Site	Gwangju
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Seoul
Korea, Republic of	GSK Investigational Site	Suwon, Kyonggi-do
Korea, Republic of	GSK Investigational Site	Uijeongbu-si, Kyonggi-do
Mexico	GSK Investigational Site	Durango
Mexico	GSK Investigational Site	Monterrey	Nuevo León
Mexico	GSK Investigational Site	Pachuca	Hidalgo
Mexico	GSK Investigational Site	Tijuana	Baja California Norte
Pakistan	GSK Investigational Site	Karachi
Pakistan	GSK Investigational Site	Lahore
Philippines	GSK Investigational Site	Cebu City
Philippines	GSK Investigational Site	Manila
Philippines	GSK Investigational Site	Manila
Philippines	GSK Investigational Site	Marikina City
Philippines	GSK Investigational Site	Quezon City
Taiwan	GSK Investigational Site	Changhua
Taiwan	GSK Investigational Site	Kaohsiung
Taiwan	GSK Investigational Site	Taichung
Taiwan	GSK Investigational Site	Taipei
Taiwan	GSK Investigational Site	Taoyuan Hsien
United States	GSK Investigational Site	Albuquerque	New Mexico
United States	GSK Investigational Site	Alhambra	California
United States	GSK Investigational Site	Artesia	California
United States	GSK Investigational Site	Avon	Indiana
United States	GSK Investigational Site	Beaver	Pennsylvania
United States	GSK Investigational Site	Billings	Montana
United States	GSK Investigational Site	Burke	Virginia
United States	GSK Investigational Site	Canal Fulton	Ohio
United States	GSK Investigational Site	Canton	Ohio
United States	GSK Investigational Site	Chaska	Minnesota
United States	GSK Investigational Site	Clairton	Pennsylvania
United States	GSK Investigational Site	Cleveland	Ohio
United States	GSK Investigational Site	Clinton	South Carolina
United States	GSK Investigational Site	Coatsville	Pennsylvania
United States	GSK Investigational Site	Columbia	South Carolina
United States	GSK Investigational Site	Columbus	Ohio
United States	GSK Investigational Site	Corpus Christi	Texas
United States	GSK Investigational Site	Dallas	Texas
United States	GSK Investigational Site	East Syracuse	New York
United States	GSK Investigational Site	Elkridge	Maryland
United States	GSK Investigational Site	Erie	Pennsylvania
United States	GSK Investigational Site	Evansville	Indiana
United States	GSK Investigational Site	Evansville	Indiana
United States	GSK Investigational Site	Excelsior Springs	Missouri
United States	GSK Investigational Site	Flushing	New York
United States	GSK Investigational Site	Georgetown	Texas
United States	GSK Investigational Site	Gig Harbor	Washington
United States	GSK Investigational Site	Gilbert	Arizona
United States	GSK Investigational Site	Glendale	Arizona
United States	GSK Investigational Site	Graham	Washington
United States	GSK Investigational Site	Greenbrae	California
United States	GSK Investigational Site	Hamilton	New Jersey
United States	GSK Investigational Site	Hialeah	Florida
United States	GSK Investigational Site	Huntersville	North Carolina
United States	GSK Investigational Site	Indianapolis	Indiana
United States	GSK Investigational Site	Kahului	Hawaii
United States	GSK Investigational Site	Kettering	Ohio
United States	GSK Investigational Site	Kingsport	Tennessee
United States	GSK Investigational Site	Kingston	New York
United States	GSK Investigational Site	Las Vegas	Nevada
United States	GSK Investigational Site	Manassas	Virginia
United States	GSK Investigational Site	Minneapolis	Minnesota
United States	GSK Investigational Site	Mogadore	Ohio
United States	GSK Investigational Site	Ocala	Florida
United States	GSK Investigational Site	Olympia	Washington
United States	GSK Investigational Site	Oregon City	Oregon
United States	GSK Investigational Site	Pahrump	Nevada
United States	GSK Investigational Site	Pelzer	South Carolina
United States	GSK Investigational Site	Peoria	Illinois
United States	GSK Investigational Site	Phoenix	Arizona
United States	GSK Investigational Site	Roseville	California
United States	GSK Investigational Site	Sacramento	California
United States	GSK Investigational Site	Salem	Virginia
United States	GSK Investigational Site	Sewickley	Pennsylvania
United States	GSK Investigational Site	Slidell	Louisiana
United States	GSK Investigational Site	South Burlington	Vermont
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	St. Louis	Missouri
United States	GSK Investigational Site	St. Peters	Missouri
United States	GSK Investigational Site	Sunset	Louisiana
United States	GSK Investigational Site	Tacoma	Washington
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Tucson	Arizona
United States	GSK Investigational Site	Tuscaloosa	Alabama
United States	GSK Investigational Site	Vancouver	Washington
United States	GSK Investigational Site	Wandsworth	Ohio
United States	GSK Investigational Site	Waterloo	Iowa
United States	GSK Investigational Site	Wauwatosa	Wisconsin
United States	GSK Investigational Site	Wenatchee	Washington
United States	GSK Investigational Site	West Chester	Pennsylvania
United States	GSK Investigational Site	Wheat Ridge	Colorado

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Countries where clinical trial is conducted

United States,  Argentina,  Brazil,  Canada,  Korea, Republic of,  Mexico,  Pakistan,  Philippines,  Taiwan, 

References & Publications (1)

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-naïve type 2 diabetes mellitus patients. Diabetes Obes Metab. 2011 Nov;13(11):1036-46. doi: 10.1111/j.1463-1326.2011.01461.x. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change From Baseline in HbA1c at Week 80	Blood was taken for serum HbA1c measurements. Change from baseline was calculated as the Week 80 value minus the baseline value. Last observation carried forward (LOCF) was not used for this analysis.	Baseline and Week 80	No
Secondary	Mean Change From Baseline in HbA1c at Week 80	Blood was taken for serum Hb1AC measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values.	Baseline and Week 80	No
Secondary	Number of Participants Achieving HbA1c <=6.5% and <7% at Week 80	Blood was taken for serum Hb1AC measurements. Hb1AC responders were described as participants having achieved Hb1AC <=6% and <7% at Week 80 with LOCF from Week 32.	Week 80	No
Secondary	Change in Fasting Plasma Glucose (FPG) From Baseline at Week 80	Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value.	Baseline and Week 80	No
Secondary	Change From Baseline in FPG at Week 80	Blood was taken for serum FPG measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values.	Baseline and Week 80	No
Secondary	Number of Participants Achieving FPG <=6 mmol/L (110 mg/dL) and <=7 mmol/L (126 mg/dL) at Week 80	Blood was taken for serum FPG measurements. FPG responders were described as participants having achieved FPG <=6 mmol/L (110 mg/dL) and <7 mmol/L (126 mg/dL) Hb1AC at Week 80 with LOCF from Week 32.	Week 80	No
Secondary	Number of Participants Achieving Treatment Failure	Treatment failure was defined as an HbA1c level >= 7% after Week 32 or withdrawal due to insufficient therapeutic effect (ITE) at any time.	Randomization to treatment failure (up to Week 80)	No
Secondary	Percent Change From Baseline in Total Cholesterol, Low-density Lipoprotein (LDL) Cholesterol, High-density Lipoprotein (HDL) Cholesterol, and Triglycerides at Week 80	Blood was taken for measurement of total cholesterol, LDL cholesterol, HDL cholesterol, and triglycerides. Percent change from baseline at Week 80 was based on log transformed data. Geometric mean, GM; standard error, SE. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Week 80	No
Secondary	Percent Change From Baseline in Adiponectin at Week 80 (United States [US] and Mexico Subset of Participants )	Blood was taken for measurement of adiponectin. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Percent Change From Baseline in C-reactive Protein (CRP) at Week 80 (US and Mexico Subset of Participants)	Blood was taken for measurement of CRP. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Percent Change in Free Fatty Acids (FFA) From Baseline at Week 80 (US and Mexico Subset of Participants).	Blood was taken for measurement of FFA. Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Change in Fasting Insulin From Baseline at Week 80 (US and Mexico Subset of Participants)	Blood was taken for fasting insulin measurements. Change from baseline was calculated as the Week 80 value minus the baseline value, with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Change in C-peptide From Baseline at Week 80 (US and Mexico Subset of Participants)	Blood was taken for C-peptide measurements. Change from baseline was calculated as the Week 80 value minus the baseline value with LOCF from Week 32 for withdrawn participants or missing values. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Percent Change From Baseline in in HOMA-S and HOMA-B to Week 80 (US and Mexico Subset of Participants)	Blood was taken for measurement of homeostasis model assessment for insulin sensitivity (HOMA-S) and beta-cell function (HOMA-B). Percent change from baseline at Week 80 was based on log transformed data. This outcome measure was analyzed for a subset of participants in the US and Mexico only. GM, geometric mean; SE, standard error.	Baseline and Week 80	No
Secondary	Slope of Delta-cell Function as Estimated by the Ratio deltaI/deltaG	The ratio Delta I/Delta G is calculated based on the oral glucose tolerance test (OGTT), where Delta I = (30 minute immunoreactive insulin minus 0 minute immunoreactive insulin) and Delta G = (30 minute plasma glucose minus 0 minute plasma glucose). The 0 minute values are fasting insulin and glucose; the 30 minute values are taken 30 minutes after the oral glucose challenge. This outcome measure was analyzed for a subset of participants in the US and Mexico only.	Baseline and Week 80	No
Secondary	Number of Participants at Final Dose Level		Baseline to Week 80 or withdrawal	No
Secondary	Percent Change From Baseline in Lumbar Spine Bone Mass Density (BMD) at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100%. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Total Hip BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Trochanter BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Femoral Neck BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Distal Radius BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Total Body BMD at Weeks 20, 56, and 80 (Bone Sub-study Subset of Participants)	BMD was measured by dual X-ray absorptiometry (DXA). The percent change from baseline in BMD at a given timepoint was defined at the participant level by the following formula: percent change = (BMD at given week minus BMD at baseline)/BMD at baseline x 100. This outcome measure was analyzed for a subset of participants in the bone study only.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Serum Calcium at Weeks 12, 32, 56, and 80	Blood was taken for measurement of serum calcium. Percent change from baseline was based on log transformed data. Geometric mean, GM; standard error, SE. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Weeks 12, 32, 56, and 80	No
Secondary	Percent Change From Baseline in Intact Parathyroid Hormone at Week 80	Blood was taken for measurement of intact parathyroid hormone. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Week 80	No
Secondary	Percent Change From Baseline in 25-hydroxy Vitamin D at Week 80	Blood was taken for measurement of 25-hydroxy vitamin D. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Week 80	No
Secondary	Percent Change From Baseline in Estradiol at Weeks 20, 56, and 80	Blood was taken for measurement of estradiol. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of female participants in the bone study only. n is the number of evaluable participants, which is the number of female participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in C-terminal Telopeptide (CTX) at Weeks 20, 56, and 80	Blood was taken for measurement of CTX. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Procollagen Type-1 N-propeptide (P1NP) at Weeks 20, 56, and 80	Blood was taken for measurement of P1NP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Weeks 20, 56, and 80	No
Secondary	Percent Change From Baseline in Bone Alkaline Phosphatase (BSAP) at Weeks 20, 56, and 80	Blood was taken for measurement of BSAP. Percent change from baseline was based on log transformed data. Standard error, SE; Wk, Week; %, percent. This outcome measure was analyzed for a subset of participants in the bone study only. n is the number of evaluable participants, which is the number of participants with a value at baseline and at the specified visit for the parameter of interest.	Baseline and Weeks 20, 56, and 80	No