A Study in Indian Postmenopausal Women With Osteoporosis to Evaluate the Efficacy and Safety of Denosumab

• Sponsor: GlaxoSmithKline (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01495000
• Collaborator: (none)
• Enrollment: 250
• Locations: 11
• Arms: 2
• Duration (Months): 13
• Patients Per Site: 22.7
• Patients Per Site Per Month: 1.7

Study Details

Study Description

Brief Summary

The purpose of this study is to determine if denosumab is effective in increasing bone mineral density at the lumbar spine in Indian postmenopausal women with osteoporosis.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis, Postmenopausal	Drug: denosumab; Drug: placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 250 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Six-Month Randomized, Double-Blind, Placebo-Controlled, Parallel-Group, Multicenter Study to Evaluate the Efficacy and Safety of Denosumab in Indian Postmenopausal Women With Osteoporosis
• Study Start Date: Jan 1, 2012
• Actual Primary Completion Date: Feb 1, 2013
• Actual Study Completion Date: Feb 1, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Arm 1 denosumab 60mg subcutaneous injection, single dose at the start of the 6-month double-blind treatment	Drug: denosumab; 60mg subcutaneous injection, single dose
Placebo Comparator: Arm 2 placebo subcutaneous injection, single dose at the start of the 6-month double-blind treatment	Drug: placebo; placebo subcutaneous injection, single dose

Outcome Measures

Primary Outcome Measures

1. Mean Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 6 [Baseline and Month 6]

   Bone mineral density (BMD) at the lumbar spine was measured by the dual-energy x-ray absorptiometry (DXA) scanner. The mean percent change from Baseline in BMD was calculated as: (value at Month 6 minus Baseline value) * 100 / Baseline value. Analysis was performed using an Analysis of Covariance (ANCOVA) model with terms for treatment and baseline BMD at the lumbar spine (as a continuous covariate).

Secondary Outcome Measures

1. Mean Percent Change From Baseline in BMD at the Total Hip, Femoral Neck, and Trochanter at Month 6 [Baseline and Month 6]

   BMD at the total hip, femoral neck, and trochanter was measured by the DXA scanner. The mean percent change from Baseline in BMD was calculated as: (value at Month 6 minus Baseline value) * 100 / Baseline value. Analysis was performed using an ANCOVA model with terms for treatment and corresponding Baseline BMD (as a continuous covariate).

2. Median Percent Change From Baseline in Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen (s-CTX) and Serum Procollagen Type IN Propeptide (s-PINP) Markers at Months 1, 3, and 6 [Baseline; Months 1, 3, and 6]

   Blood samples were collected for the measurement of s-CTx and s-PINP, which are used as biomarkers of bone resorption and formation, respectively. The median percent change from Baseline in s-CTX and s-PINP markers at Months 1, 3, and 6 was calculated as: (post-Baseline value minus Baseline value) * 100 / Baseline value.

3. Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE) [From Baseline up to Month 6]

   An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury with hyperbilirubinaemia. Medical or scientific judgment was to have been exercised in other important medical events. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.

4. Number of Participants With a Change From Baseline in Vital Signs of Potential Clinical Concern at Months 1, 3, and 6 [Baseline; Months 1, 3, and 6]

   Vital sign values of potential clinical concern were defined as: change in heart rate >30 beats per minutes (bpm), change in systolic blood pressure (SBP) >30 millimeters of mercury (mmHg), and change in diastolic blood pressure (DBP) >20 mmHg. The number of participants with post-Baseline vital sign values of potential clinical concern who did not have values of potential clinical concern at Baseline are summarized. If the change from Baseline is a decrease greater than the threshold, it is categorized as "low." If the change from Baseline is an increase greater than the threshold, it is categorized ad "high."

5. Number of Participants With the Indicated Laboratory Parameter Values of Potential Clinical Concern at Month 6 [Month 6]

   The number of participants with laboratory parameter values of potential clinical concern at Month 6 are summarized. The following are the laboratory values of potential clinical concern: alkaline phosphatase, High: >375 units/Liter (L); aspartate aminotransferase, High: >165 units/L; creatinine, High: >159 micromoles (µmol)/L; glucose, Low: <3 millimoles (mmol)/L; hematocrit, Low: <0.325; hemoglobin, Low: <91grams/L; phosphorus, High: >1.723 mmol/L; potassium, High: >6.3 mmol/L; sodium, Low: <130 mmol/L; total neutrophils, Low: <0.9 10^9 cells (GI)/L; blood urea nitrogen (BUN), High: >21mmol/L; uric acid, High: 654 µmol/L.

6. Change From Baseline in Albumin/Globulin Ratio and Blood Urea Nitrogen (BUN)/Creatinine Ratio at Month 6 [Baseline and Month 6]

   Blood samples were collected for the measurement of albumin/globulin ratio and BUN/creatinine ratio values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

7. Change From Baseline in Albumin, Hemoglobin, Mean Corpuscle Hemoglobin Concentration (Conc.), and Total Protein at Month 6 [Baseline and Month 6]

   Blood samples were collected for the measurement of albumin, hemoglobin, mean corpuscle hemoglobin concentration, and total protein values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

8. Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatinine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase at Month 6 [Baseline and Month 6]

   Blood samples were collected for the measurement of alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatinine kinase, gamma glutamyl transferase, and lactate dehydrogenase values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

9. Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Segmented Neutrophils, Total Neutrophils, Platelet Count, and White Blood Cell Count Month 6 [Baseline and Month 6]

   Blood samples were collected for the measurement of basophil, eosinophil, lymphocyte, monocyte, segmented neutrophil, total neutrophil, platelet count, and white blood cell count values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

10. Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Creatinine, and Uric Acid at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of direct bilirubin, indirect bilirubin, total bilirubin, creatinine, and uric acid values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

11. Change From Baseline in Calcium Corrected, Calcium, Chloride, Glucose, Potassium, Magnesium, Sodium, Phosphorus Inorganic, Triglycerides, Urea/BUN, and Very Low-density Lipoproteins (VLDL) Cholesterol Calculation at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of calcium corrected, calcium, chloride, glucose, potassium, magnesium, sodium, phosphorus inorganic, triglyceride, urea/BUN, and VLDL cholesterol calculation values. Change from Baseline was calcualted as the Month 6 value minus the Baseline value.

12. Change From Baseline in Hematocrit at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of hematocrit values. Change from Baseline was calculated as the Month 6 value minuse the Baseline value.

13. Change From Baseline in Mean Corpuscle Hemoglobin at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of hemoglobin values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

14. Change From Baseline in Mean Corpuscular Volume at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of mean corpuscular volume values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

15. Change From Baseline in Red Blood Cell Count at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of red blood cell count values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

16. Change From Baseline in Red Cell Distribution Width at Month 6 [Baseline and Month 6]

    Blood samples were collected for the measurement of red cell distribution width values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.

17. Number of Participants With Positive and Negative Results for Anti-body Formation to Denosumab at Month 6 [Month 6]

    The number of participants with positive and negative results for both neutralizing antibodies to denosumab and for binding antibodies to denosumab at Month 6 are summarized.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 55 Years to 75 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Ambulatory Indian postmenopausal women with osteoporosis

• greater than 5 years postmenopausal

• aged 55 to 75 years old

• absolute bone mineral density value consistent with a T-score less than -2.5 and greater than - 4.0 at the either the lumbar spine or total hip, as measured by dual energy x-ray absorptiometry. Subjects with a T-score less than or equal to -4.0 are at very high risk for fracture and will be excluded.

Exclusion Criteria:

• previous or current metabolic bone disease, Paget's or Cushing's disease, or hyperprolactinemia

• current hypo- or hyperparathyroidism or hypo- or hyperthyroidism unless on stable thyroid replacement therapy and TSH level meets criteria

• rheumatoid arthritis

• cirrhosis of the liver or unstable liver disease or ALT or AST greater than or equal to 2.0 times the upper limit of normal, or alkaline phosphatase and bilirubin greater than or equal to 1.5 times the upper limit of normal

• medications used to treat osteoporosis, defined for type and duration of use, and including IV and oral bisphosphonates

• medications that affect bone metabolism including parathyroid hormone or derivatives; anabolic steroids or testosterone; glucocorticosteroids; systemic hormone replacement therapy; selective estrogen receptor modulators; tibolone, calcitonin, and calcitriol or vitamin D derivatives; other bone active drugs including anticonvulsives (but not benzodiazepines) and heparin; chronic systemic ketoconazole, androgens, ACTH, cinacalcet, aluminum, lithium, protease inhibitors, methotrexate, and gonadotropin-releasing hormone agonists

• malignancy within 5 years except certain resected types

• malabsorption syndrome or gastrointestinal disorders associated with malabsorption

• abnormal calcium level

• vitamin D deficiency

• any laboratory abnormality that will prevent the subject from completing the study or interferes with interpretation of study results

• oral or dental conditions including current or past history of osteomyelitis or osteonecrosis of the jaw; active dental or jaw condition with requires oral surgery; planned invasive dental procedure; un-healed dental or oral surgery

• any disorder that compromises the ability of the subject to give written informed consent or to comply with study procedures

• any physical or psychiatric disorder that will prevent the subject from completing the study or interferes with study results

• known to have tested positive for HIV

• less than two lumbar vertebrae evaluable for DXA measurements

• height, weight, or girth that may preclude accurate DXA measurements

• drug or alcohol abuse within 12 months that interferes with understanding or completing the study

• known sensitivity to mammalian cell-derived drug products

• use of an investigational drug or device within 30 days of enrollment or currently receiving other investigational agent(s)

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	GSK Investigational Site	Ahmedabad		India	380015
2	GSK Investigational Site	Bangalore		India	560043
3	GSK Investigational Site	Bangalore		India	560052
4	GSK Investigational Site	Bangalore		India	560054
5	GSK Investigational Site	Delhi		India	110060
6	GSK Investigational Site	Mangalore		India	575002
7	GSK Investigational Site	Nagpur		India	440010
8	GSK Investigational Site	Nagpur		India	440012
9	GSK Investigational Site	Pune		India	411030
10	GSK Investigational Site	Trivandrum		India	695011
11	GSK Investigational Site	Vadodra		India	390007

Sponsors and Collaborators

• GlaxoSmithKline

Investigators

• Study Director: GSK Clinical Trials, GlaxoSmithKline

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: GlaxoSmithKline
• ClinicalTrials.gov Identifier: NCT01495000
• Other Study ID Numbers: 114161
• First Posted: Dec 19, 2011
• Last Update Posted: Feb 7, 2014
• Last Verified: Dec 1, 2013

• Keywords provided by GlaxoSmithKline: India; dual energy x-ray absorptiometry; bone mineral density; denosumab
• Additional relevant MeSH terms: Osteoporosis; Osteoporosis, Postmenopausal; Denosumab

Study Results

Participant Flow

Pre-assignment Detail	The study consisted of a Screening Phase of up to 2.5 months and a 6-month Double-blind Treatment Phase. A total of 551 participants (par.) were screened; 303 par. were screen failures, and 250 par. were randomized (2 par. were considered to be screen failures; however, these par. were randomized, 1 to each treatment group).

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Period Title: Overall Study
STARTED	124	126
COMPLETED	111	114
NOT COMPLETED	13	12

Baseline Characteristics

Arm/Group Title	Denosumab 60 mg	Placebo	Total
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).	Total of all reporting groups
Overall Participants	124	126	250
Age (Years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [Years]	62.6 (5.10)	62.6 (4.85)	62.6 (4.96)
Sex: Female, Male (Count of Participants)
Female	124 100%	126 100%	250 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (participants) [Number]
Asian - Central/South Asian Heritage	124 100%	126 100%	250 100%

Outcome Measures

1. Primary Outcome

Title	Mean Percent Change From Baseline in Bone Mineral Density at the Lumbar Spine at Month 6
Description	Bone mineral density (BMD) at the lumbar spine was measured by the dual-energy x-ray absorptiometry (DXA) scanner. The mean percent change from Baseline in BMD was calculated as: (value at Month 6 minus Baseline value) * 100 / Baseline value. Analysis was performed using an Analysis of Covariance (ANCOVA) model with terms for treatment and baseline BMD at the lumbar spine (as a continuous covariate).
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

Intent-to-Treat Efficacy (ITTE) Population: all randomized participants who received one dose of study medication, and who had a Baseline measure and at least one post-Baseline efficacy measure during the Double-blind Treatment Phase. Only participants with BMD values at both Baseline and Month 6 were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	100	105
Least Squares Mean (Standard Error) [percent change]	4.26 (0.413)	1.20 (0.403)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Denosumab 60 mg, Placebo
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	Comments
	Method	ANCOVA
	Comments
Method of Estimation	Estimation Parameter	Mean Difference (Final Values)
	Estimated Value	3.05
	Confidence Interval	(2-Sided) 95%; 1.91 to 4.19
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Mean Percent Change From Baseline in BMD at the Total Hip, Femoral Neck, and Trochanter at Month 6
Description	BMD at the total hip, femoral neck, and trochanter was measured by the DXA scanner. The mean percent change from Baseline in BMD was calculated as: (value at Month 6 minus Baseline value) * 100 / Baseline value. Analysis was performed using an ANCOVA model with terms for treatment and corresponding Baseline BMD (as a continuous covariate).
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITTE Population. Only participants with BMD values at both Baseline and Month 6 were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	87	86
Total Hip	2.02 (0.270)	0.32 (0.271)
Femoral Neck	2.69 (0.407)	0.40 (0.409)
Trochanter	2.49 (0.366)	0.69 (0.368)

3. Secondary Outcome

Title	Median Percent Change From Baseline in Serum Carboxy-terminal Cross-linking Telopeptide of Type I Collagen (s-CTX) and Serum Procollagen Type IN Propeptide (s-PINP) Markers at Months 1, 3, and 6
Description	Blood samples were collected for the measurement of s-CTx and s-PINP, which are used as biomarkers of bone resorption and formation, respectively. The median percent change from Baseline in s-CTX and s-PINP markers at Months 1, 3, and 6 was calculated as: (post-Baseline value minus Baseline value) * 100 / Baseline value.
Time Frame	Baseline; Months 1, 3, and 6

Outcome Measure Data

Analysis Population Description

ITTE Population. Only participants with s-CTX and s-PINP values at both Baseline and Months 1, 3, and 6 were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points/for different parameters, so the overall number of participants analyzed reflects the entire ITTE Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	121	123
s-CTx, Month 1, n=112, 121	-80.61	-17.01
s-CTx, Month 3, n=107, 113	-82.43	-18.97
s-CTx, Month 6, n=105, 113	-62.5	-28.82
s-PINP, Month 1, n=110, 120	-34.55	-13.62
s-PINP, Month 3, n=107, 111	-78.08	-27.87
s-PINP, Month 6, n=104, 113	-63.41	-25.81

4. Secondary Outcome

Title	Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)
Description	An AE is defined as any untoward medical occurrence in a participant, temporally associated with the use of a medicinal product, whether or not considered related to the medicinal product. An SAE is defined as any untoward medical occurrence that, at any dose, results in death, is life threatening, requires hospitalization or prolongation of existing hospitalization, results in disability/incapacity, is a congenital anomaly/birth defect, or is an event of possible drug-induced liver injury with hyperbilirubinaemia. Medical or scientific judgment was to have been exercised in other important medical events. Refer to the general Adverse AE/SAE module for a complete list of AEs and SAEs.
Time Frame	From Baseline up to Month 6

Outcome Measure Data

Analysis Population Description

ITT Population: all participants who received one dose of study medication

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Any AE	38 30.6%	47 37.3%
Any SAE	1 0.8%	3 2.4%

5. Secondary Outcome

Title	Number of Participants With a Change From Baseline in Vital Signs of Potential Clinical Concern at Months 1, 3, and 6
Description	Vital sign values of potential clinical concern were defined as: change in heart rate >30 beats per minutes (bpm), change in systolic blood pressure (SBP) >30 millimeters of mercury (mmHg), and change in diastolic blood pressure (DBP) >20 mmHg. The number of participants with post-Baseline vital sign values of potential clinical concern who did not have values of potential clinical concern at Baseline are summarized. If the change from Baseline is a decrease greater than the threshold, it is categorized as "low." If the change from Baseline is an increase greater than the threshold, it is categorized ad "high."
Time Frame	Baseline; Months 1, 3, and 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points/for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
DBP, Month 1: High, n=122, 125	1 0.8%	2 1.6%
DBP, Month 1: Low, n=122, 125	1 0.8%	4 3.2%
DBP, Month 3: High, n=117, 120	2 1.6%	0 0%
DBP, Month 3: Low, n=117, 120	0 0%	2 1.6%
DBP, Month 6: Low, n=111, 114	0 0%	3 2.4%
SBP, Month 1: Low, n=122, 125	1 0.8%	2 1.6%
SBP, Month 3: High, n=117, 120	1 0.8%	1 0.8%
SBP, Month 3: Low, n=117, 120	1 0.8%	3 2.4%
SBP, Month 6: Low, n=111, 114	2 1.6%	3 2.4%
Heart Rate, Month 3: Low, n=117, 120	0 0%	1 0.8%

6. Secondary Outcome

Title	Number of Participants With the Indicated Laboratory Parameter Values of Potential Clinical Concern at Month 6
Description	The number of participants with laboratory parameter values of potential clinical concern at Month 6 are summarized. The following are the laboratory values of potential clinical concern: alkaline phosphatase, High: >375 units/Liter (L); aspartate aminotransferase, High: >165 units/L; creatinine, High: >159 micromoles (µmol)/L; glucose, Low: <3 millimoles (mmol)/L; hematocrit, Low: <0.325; hemoglobin, Low: <91grams/L; phosphorus, High: >1.723 mmol/L; potassium, High: >6.3 mmol/L; sodium, Low: <130 mmol/L; total neutrophils, Low: <0.9 10^9 cells (GI)/L; blood urea nitrogen (BUN), High: >21mmol/L; uric acid, High: 654 µmol/L.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed at different time points/for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Alkaline phosphatase: High, n=107, 114	0 0%	1 0.8%
Aspartate aminotransferase: High, n=107, 113	1 0.8%	0 0%
Creatinine: High, n=107, 114	1 0.8%	1 0.8%
Glucose: Low, n=107, 114	1 0.8%	0 0%
Hematocrit: Low, n=106, 111	1 0.8%	1 0.8%
Hemoglobin: Low, n=106, 111	2 1.6%	3 2.4%
Inorganic Phosphorus: High, n=107, 114	0 0%	1 0.8%
Potassium: High, n=107, 113	1 0.8%	0 0%
Sodium: Low, n=107, 114	0 0%	1 0.8%
Total Neutrophils: Low, n=104, 107	0 0%	2 1.6%
Urea/BUN: High, n=107, 114	0 0%	1 0.8%
Uric Acid: High, n=107, 114	0 0%	1 0.8%

7. Secondary Outcome

Title	Change From Baseline in Albumin/Globulin Ratio and Blood Urea Nitrogen (BUN)/Creatinine Ratio at Month 6
Description	Blood samples were collected for the measurement of albumin/globulin ratio and BUN/creatinine ratio values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	114
Albumin/globulin ratio	0.025 (0.1446)	0.018 (0.1518)
BUN/creatinine ratio	-5.896 (18.0195)	-1.860 (19.8400)

8. Secondary Outcome

Title	Change From Baseline in Albumin, Hemoglobin, Mean Corpuscle Hemoglobin Concentration (Conc.), and Total Protein at Month 6
Description	Blood samples were collected for the measurement of albumin, hemoglobin, mean corpuscle hemoglobin concentration, and total protein values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Albumin, n=106, 114	0.689 (2.4470)	0.746 (2.9020)
Hemoglobin, n=106, 107	2.236 (6.2891)	1.925 (8.4927)
Mean corpuscle hemoglobin conc., n=106, 107	2.321 (9.8653)	1.607 (10.0196)
Total protein, n=106, 114	0.585 (3.8219)	0.886 (4.1621)

9. Secondary Outcome

Title	Change From Baseline in Alkaline Phosphatase, Alanine Amino Transferase, Aspartate Amino Transferase, Creatinine Kinase, Gamma Glutamyl Transferase, and Lactate Dehydrogenase at Month 6
Description	Blood samples were collected for the measurement of alkaline phosphatase, alanine amino transferase, aspartate amino transferase, creatinine kinase, gamma glutamyl transferase, and lactate dehydrogenase values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Alkaline phosphatase, n=106, 114	-18.179 (25.0207)	-3.684 (41.4420)
Alanine amino transferase, n=106, 114	2.481 (10.2421)	0.035 (15.6640)
Aspartate amino transferase, 106, 113	2.755 (10.9465)	-0.965 (16.9226)
Creatinine kinase, n=106, 114	6.170 (51.2968)	11.175 (63.0331)
Gamma glutamyl transferase, n=106, 114	2.915 (12.8346)	-0.754 (13.8433)
Lactate dehydrogenase, n=106, 113	2.764 (25.2811)	0.434 (36.7389)

10. Secondary Outcome

Title	Change From Baseline in Basophils, Eosinophils, Lymphocytes, Monocytes, Segmented Neutrophils, Total Neutrophils, Platelet Count, and White Blood Cell Count Month 6
Description	Blood samples were collected for the measurement of basophil, eosinophil, lymphocyte, monocyte, segmented neutrophil, total neutrophil, platelet count, and white blood cell count values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Basophils, n=104, 103	0.001 (0.0221)	-0.001 (0.0262)
Eosinophils, n=104, 103	-0.076 (0.2794)	-0.001 (0.3414)
Lymphocytes, n=104, 103	-0.065 (0.6044)	-0.056 (0.7476)
Monocytes, n=104, 103	0.000 (0.1204)	0.032 (0.1727)
Segmented neutrophils, n=104, 103	-0.290 (1.6142)	-0.129 (1.7405)
Total neutrophils, n=104, 103	-0.297 (1.6099)	-0.135 (1.7343)
Platelet count, n=103, 105	3.117 (38.5322)	7.533 (36.5761)
White blood cell count, n=104, 103	-0.436 (1.6614)	-0.160 (1.7629)

11. Secondary Outcome

Title	Change From Baseline in Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Creatinine, and Uric Acid at Month 6
Description	Blood samples were collected for the measurement of direct bilirubin, indirect bilirubin, total bilirubin, creatinine, and uric acid values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Direct bilirubin, n=105, 112	0.152 (1.1667)	0.089 (1.2122)
Indirect bilirubin, n=105, 112	0.210 (2.7305)	-0.054 (2.2050)
Total bilirubin, n=106, 114	0.358 (2.8659)	0.000 (2.2102)
Creatinine, n=106, 114	2.337 (11.8458)	3.041 (13.1471)
Uric acid, n=106, 114	-2.642 (60.6677)	-6.316 (61.9058)

12. Secondary Outcome

Title	Change From Baseline in Calcium Corrected, Calcium, Chloride, Glucose, Potassium, Magnesium, Sodium, Phosphorus Inorganic, Triglycerides, Urea/BUN, and Very Low-density Lipoproteins (VLDL) Cholesterol Calculation at Month 6
Description	Blood samples were collected for the measurement of calcium corrected, calcium, chloride, glucose, potassium, magnesium, sodium, phosphorus inorganic, triglyceride, urea/BUN, and VLDL cholesterol calculation values. Change from Baseline was calcualted as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed (represented by n=X, X in the category titles). Different participants may have been analyzed for different parameters, so the overall number of participants analyzed reflects the entire ITT Population.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	124	126
Calcium corrected, n=12, 24	0.015 (0.0573)	0.008 (0.0755)
Calcium, n=106, 113	0.012 (0.1194)	0.033 (0.1069)
Chloride, n=106, 114	-0.802 (3.0376)	-0.895 (3.0552)
Glucose, n=106, 113	-0.571 (2.2401)	-0.303 (2.6346)
Potassium, n=106, 113	0.140 (0.4581)	0.158 (0.4118)
Magnesium, n=106, 114	0.009 (0.0718)	0.009 (0.0614)
Sodium, n=106, 114	-0.472 (2.2979)	-0.395 (2.5921)
Phosphorus inorganic, n=106, 114	-0.052 (0.2047)	-0.012 (0.1674)
Triglycerides, n=106, 114	-0.305 (0.7413)	-0.263 (0.8433)
Urea/BUN, n=106, 114	-0.283 (1.1423)	0.114 (2.2032)
VLDL cholesterol calculation, n=103, 109	-0.131 (0.3178)	-0.105 (0.3504)

13. Secondary Outcome

Title	Change From Baseline in Hematocrit at Month 6
Description	Blood samples were collected for the measurement of hematocrit values. Change from Baseline was calculated as the Month 6 value minuse the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	107
Mean (Standard Deviation) [proportion of RBCs in blood]	0.004 (0.0204)	0.004 (0.0264)

14. Secondary Outcome

Title	Change From Baseline in Mean Corpuscle Hemoglobin at Month 6
Description	Blood samples were collected for the measurement of hemoglobin values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	107
Mean (Standard Deviation) [picograms]	0.407 (0.8613)	0.260 (1.2787)

15. Secondary Outcome

Title	Change From Baseline in Mean Corpuscular Volume at Month 6
Description	Blood samples were collected for the measurement of mean corpuscular volume values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	107
Mean (Standard Deviation) [femtoliters]	0.623 (2.9775)	0.327 (3.5309)

16. Secondary Outcome

Title	Change From Baseline in Red Blood Cell Count at Month 6
Description	Blood samples were collected for the measurement of red blood cell count values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	107
Mean (Standard Deviation) [10^12 cells per liter (TI/L)]	0.016 (0.2575)	0.034 (0.3034)

17. Secondary Outcome

Title	Change From Baseline in Red Cell Distribution Width at Month 6
Description	Blood samples were collected for the measurement of red cell distribution width values. Change from Baseline was calculated as the Month 6 value minus the Baseline value.
Time Frame	Baseline and Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time points were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	106	107
Mean (Standard Deviation) [percentage]	0.065 (1.2126)	-0.121 (1.2735)

18. Secondary Outcome

Title	Number of Participants With Positive and Negative Results for Anti-body Formation to Denosumab at Month 6
Description	The number of participants with positive and negative results for both neutralizing antibodies to denosumab and for binding antibodies to denosumab at Month 6 are summarized.
Time Frame	Month 6

Outcome Measure Data

Analysis Population Description

ITT Population. Only participants available at the specified time point were analyzed.

Arm/Group Title	Denosumab 60 mg	Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).	Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
Measure Participants	110	114
Neutralizing antibodies, n=0, 0	NA NaN	NA NaN
Binding antibodies, Positive, n=110, 114	0 0%	0 0%
Binding antibodies, Negative, n=110, 114	110 88.7%	114 90.5%

Adverse Events

Time Frame	SAEs (serious adverse events) and non-serious AEs were collected from the start of study medication through the study period (6-month post-dose) (up to Study Week 43).
Adverse Event Reporting Description	AEs and SAEs were collected in members of the Intent-to-Treat (ITT) Population, comprised of all participants who received one dose of study medication.
Arm/Group Title	Denosumab 60 mg		Placebo
Arm/Group Description	Participants received denosumab 60 milligrams (mg) administered as a single subcutaneous (SC) injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 international units [IU]).		Participants received placebo administered as a single subcutaneous injection at the start of the Double-blind Treatment Phase. All participants received daily oral supplementation of elemental calcium (at least 1000 mg) and vitamin D (at least 400 IU).
All Cause Mortality
	Denosumab 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Denosumab 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/124 (0.8%)		3/126 (2.4%)
Eye disorders
Cataract nuclear	1/124 (0.8%)		0/126 (0%)
General disorders
Asthenia	0/124 (0%)		1/126 (0.8%)
Infections and infestations
Liver abscess	0/124 (0%)		1/126 (0.8%)
Investigations
Hepatic enzyme increased	0/124 (0%)		1/126 (0.8%)
Vascular disorders
Hypotension	0/124 (0%)		1/126 (0.8%)
Varicose vein ruptured	0/124 (0%)		1/126 (0.8%)
Other (Not Including Serious) Adverse Events
	Denosumab 60 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/124 (6.5%)		3/126 (2.4%)
Infections and infestations
Upper respiratory tract infection	8/124 (6.5%)		3/126 (2.4%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

GSK agreements may vary with individual investigators, but will not prohibit any investigator from publishing. GSK supports the publication of results from all centers of a multi-center trial but requests that reports based on single-site data not precede the primary publication of the entire clinical trial.