A Study to Assess Safety and Efficacy of Odanacatib (MK-0822) in Men With Osteoporosis (MK-0822-053)

• Sponsor: Merck Sharp & Dohme LLC (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01120600
• Collaborator: (none)
• Enrollment: 294
• Arms: 2
• Actual Duration (Months): 37.4

Study Details

Study Description

Brief Summary

The purpose of this study is to test the hypothesis that treatment with odanacatib will result in increased bone mineral density (BMD) compared to treatment with placebo. This study will also evaluate the safety and efficacy of odanacatib for male osteoporosis participants.

Condition or Disease	Intervention/Treatment	Phase
Osteoporosis	Drug: Odanacatib; Drug: Placebo for Odanacatib; Dietary Supplement: Vitamin D3; Dietary Supplement: Calcium carbonate	Phase 3

Detailed Description

The original study was divided into two parts, with the primary analysis of endpoints to occur at 24 months and participants will then remain in the study for an additional 12 months (Part 2). Amendment 1 of the protocol removed the additional 12 month period and the Month 36 BMD analysis was deleted.

Study Design

• Study Type: Interventional
• Actual Enrollment: 294 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: A Phase III Randomized, Placebo-Controlled Clinical Trial to Assess the Safety and Efficacy of Odanacatib (MK-0822) in the Treatment of Men With Osteoporosis Treated With Vitamin D and Calcium
• Actual Study Start Date: Jun 9, 2010
• Actual Primary Completion Date: Jul 22, 2013
• Actual Study Completion Date: Jul 22, 2013

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Odanacatib 50 mg once weekly Participants will receive one Odanacatib 50 mg tablet once weekly. In addition, they will receive a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources is approximately 1200 mg.	Drug: Odanacatib; One 50 mg tablet once weekly; Other Names: MK-0822 ; Dietary Supplement: Vitamin D3; 5600 IU of open-label Vitamin D3 once weekly; Dietary Supplement: Calcium carbonate; Sufficient amount of open-label calcium carbonate so that daily calcium intake from both dietary and supplementary sources in approximately 1200 mg
Placebo Comparator: Placebo once weekly Participants will receive one Placebo tablet once weekly. In addition, they will receive a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources is approximately 1200 mg.	Drug: Placebo for Odanacatib; One 50 mg tablet once weekly; Dietary Supplement: Vitamin D3; 5600 IU of open-label Vitamin D3 once weekly; Dietary Supplement: Calcium carbonate; Sufficient amount of open-label calcium carbonate so that daily calcium intake from both dietary and supplementary sources in approximately 1200 mg

Outcome Measures

Primary Outcome Measures

1. Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 24 [Baseline and Month 24]

   Lumbar spine BMD was assessed by dual energy X-ray absorptiometry (DXA) at Baseline and at Month 24.

2. Number of Participants Who Experienced an Adverse Event (AE) [Up to 24 months (plus 14 days) after first dose of study drug]

   An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.

3. Number of Participants Who Discontinued Treatment Due to an AE [Up to 24 months after first dose of study drug]

   An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.

Secondary Outcome Measures

1. Percentage Change From Baseline in Total Hip BMD at Month 24 [Baseline and Month 24]

   Total hip BMD was assessed by DXA at Baseline and at Month 24.

2. Percentage Change From Baseline in Femoral Neck BMD at Month 24 [Baseline and Month 24]

   Femoral Neck BMD was assessed by DXA at Baseline and at Month 24.

3. Percentage Change From Baseline in Trochanter BMD at Month 24 [Baseline and Month 24]

   Trochanter BMD was assessed by DXA at Baseline and at Month 24.

4. Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 24 [Baseline and Month 24]

   Serum samples were collected to evaluate biochemical markers for s-CTx, which were measured at Baseline and at Month 24.

5. Percentage Change From Baseline in Urine Collagen N-Telopeptide/Creatinine Ratio (U-NTx/Cr) at Month 24 [Baseline and Month 24]

   Urine samples were collected to evaluate biochemical markers for u-NTx/Cr, which were measured at Baseline and at Month 24.

6. Percentage Change From Baseline in Serum Bone-Specific Alkaline Phosphatase (s-BSAP) at Month 24 [Baseline and Month 24]

   Serum samples were collected to evaluate biochemical markers for s-BSAP, which were measured at Baseline and at Month 24.

7. Percentage Change From Baseline in Serum N-Terminal Propeptides of Type I Collagen (s-P1NP) at Month 24 [Baseline and Month 24]

   Serum samples were collected to evaluate biochemical markers for s-P1NP, which were measured at Baseline and at Month 24.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years to 95 Years
• Sexes Eligible for Study: Male
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Is a male between 40 and 95 years of age

• Has osteoporosis

• Has anatomy suitable for dual energy x-ray absorptiometry (DXA) scan of the lumbar spine and and hip

• Is ambulatory

Exclusion Criteria:

• Is currently on oral bisphosphonates or other treatment for osteoporosis

• Had previous hip fragility fracture and is a candidate for standard of care therapy

• Has had a fragility fracture (vertebral or non-vertebral fractures indicating reduced bone strength) within 12 months

• Has had more then one previous vertebral fracture

• Has been diagnosed with metabolic bone disorder other than osteoporosis

• Is Vitamin D deficient

• Has a history of renal stones

• Has active parathyroid disease

• Has history of thyroid disease not well controlled by medication

• Is diagnosed with secondary osteoporosis

• Has a daily calcium intake of <1,200 mg and is unwilling to take study prescribed supplements or increase dietary intake, such that his daily calcium intake is at least 1200 mg

• Has a history of malignancy ≤5 years prior to signing informed consent

• Has been diagnosed with hypogonadism due to causes that affect multiple organ and body systems

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Merck Sharp & Dohme LLC

Investigators

• Study Director: Medical Director, Merck Sharp & Dohme LLC

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Merck Sharp & Dohme LLC
• ClinicalTrials.gov Identifier: NCT01120600
• Other Study ID Numbers: 0822-053; 2010_532
• First Posted: May 11, 2010
• Last Update Posted: Aug 28, 2018
• Last Verified: Jul 1, 2018

• Individual Participant Data (IPD) Sharing Statement: Yes
• Plan to Share IPD: Yes
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Osteoporosis; Vitamin D; Cholecalciferol; Calcium Carbonate; Calcium

Study Results

Participant Flow

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Period Title: Overall Study
STARTED	147	147
Treated	146	146
COMPLETED	128	115
NOT COMPLETED	19	32

Baseline Characteristics

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly	Total
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Total of all reporting groups
Overall Participants	147	147	294
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	68.9 (8.2)	68.7 (7.7)	68.8 (7.9)
Sex: Female, Male (Count of Participants)
Female	0 0%	0 0%	0 0%
Male	147 100%	147 100%	294 100%

Outcome Measures

1. Primary Outcome

Title	Percentage Change From Baseline in Lumbar Spine Bone Mineral Density (BMD) at Month 24
Description	Lumbar spine BMD was assessed by dual energy X-ray absorptiometry (DXA) at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of blinded study treatment and had available lumbar spine BMD data for Baseline and Month 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	112	107
Least Squares Mean (95% Confidence Interval) [Percentage change]	6.86	1.27

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A constrained full likelihood longitudinal data analysis (cLDA) method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	5.59
	Confidence Interval	(2-Sided) 95%; 4.48 to 6.7
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Percentage Change From Baseline in Total Hip BMD at Month 24
Description	Total hip BMD was assessed by DXA at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of blinded study treatment and had available total hip BMD data for Baseline and Month 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	111	105
Least Squares Mean (95% Confidence Interval) [Percentage change]	1.91	-0.11

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; 1.27 to 2.77
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Secondary Outcome

Title	Percentage Change From Baseline in Femoral Neck BMD at Month 24
Description	Femoral Neck BMD was assessed by DXA at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of blinded study treatment and had available femoral neck BMD data for Baseline and Month 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	111	105
Least Squares Mean (95% Confidence Interval) [Percentage change]	1.69	0

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.008
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	1.69
	Confidence Interval	(2-Sided) 95%; 0.45 to 2.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Secondary Outcome

Title	Percentage Change From Baseline in Trochanter BMD at Month 24
Description	Trochanter BMD was assessed by DXA at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of blinded study treatment and had available trochanter BMD data for Baseline and Month 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	111	105
Least Squares Mean (95% Confidence Interval) [Percentage change]	2.77	0.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	2.12
	Confidence Interval	(2-Sided) 95%; 0.93 to 3.3
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Percentage Change From Baseline in Serum C-Telopeptides of Type 1 Collagen (s-CTx) at Month 24
Description	Serum samples were collected to evaluate biochemical markers for s-CTx, which were measured at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who had no important deviations from the protocol that may have substantially affected the results, and had available s-CTx data for Baseline and Week 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	112	102
Least Squares Mean (95% Confidence Interval) [Percentage change]	-20.07	56.51

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	-76.58
	Confidence Interval	(2-Sided) 95%; -92.56 to -60.61
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Percentage Change From Baseline in Urine Collagen N-Telopeptide/Creatinine Ratio (U-NTx/Cr) at Month 24
Description	Urine samples were collected to evaluate biochemical markers for u-NTx/Cr, which were measured at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who had no important deviations from the protocol that may have substantially affected the results, and had available U-NTx/Cr data for Baseline and Week 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	111	102
Least Squares Mean (95% Confidence Interval) [Percentage change]	-61.43	6.65

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	< 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	-68.08
	Confidence Interval	(2-Sided) 95%; -78.1 to -58.06
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Percentage Change From Baseline in Serum Bone-Specific Alkaline Phosphatase (s-BSAP) at Month 24
Description	Serum samples were collected to evaluate biochemical markers for s-BSAP, which were measured at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who had no important deviations from the protocol that may have substantially affected the results, and had available s-BSAP data for Baseline and Week 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	114	110
Least Squares Mean (95% Confidence Interval) [Percentage change]	-5.28	2.66

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.019
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	-7.94
	Confidence Interval	(2-Sided) 95%; -14.58 to -1.31
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Percentage Change From Baseline in Serum N-Terminal Propeptides of Type I Collagen (s-P1NP) at Month 24
Description	Serum samples were collected to evaluate biochemical markers for s-P1NP, which were measured at Baseline and at Month 24.
Time Frame	Baseline and Month 24

Outcome Measure Data

Analysis Population Description

All randomized participants who had no important deviations from the protocol that may have substantially affected the results, and had available s-P1NP data for Baseline and Week 24

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	114	100
Least Squares Mean (95% Confidence Interval) [Percentage change]	-10.94	5.06

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Odanacatib 50 mg Once Weekly, Placebo Once Weekly
	Comments	A cLDA method was used for this statistical analysis. The cLDA model included the baseline measurement and all post-baseline percent changes from baseline in the response vector, with fixed effects for treatment, time, geographic region, machine type and treatment-by-time interaction, geographic region-by-time interaction, and machine type-by-time interaction.
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.001
	Comments
	Method	cLDA
	Comments
Method of Estimation	Estimation Parameter	Difference in Least Squares Means
	Estimated Value	-16
	Confidence Interval	(2-Sided) 95%; -25.74 to -6.27
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Primary Outcome

Title	Number of Participants Who Experienced an Adverse Event (AE)
Description	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Time Frame	Up to 24 months (plus 14 days) after first dose of study drug

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	146	146
Number [Participants]	113 76.9%	114 77.6%

10. Primary Outcome

Title	Number of Participants Who Discontinued Treatment Due to an AE
Description	An AE is defined as any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease temporally associated with the use of a study drug, whether or not it is considered related to the study drug.
Time Frame	Up to 24 months after first dose of study drug

Outcome Measure Data

Analysis Population Description

All randomized participants who took at least one dose of study drug

Arm/Group Title	Odanacatib 50 mg Once Weekly	Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.	Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
Measure Participants	146	146
Number [Participants]	5 3.4%	6 4.1%

Adverse Events

Time Frame	Up to 24 months (plus 14 days) after first dose of study drug
Adverse Event Reporting Description	All randomized participants who took at least one dose of study drug
Arm/Group Title	Odanacatib 50 mg Once Weekly		Placebo Once Weekly
Arm/Group Description	Participants received one Odanacatib 50 mg tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.		Participants received one Placebo tablet once weekly. In addition, they received a weekly dose 5600 IU of open-label Vitamin D3 as well as a sufficient supply of open-label calcium carbonate so that their total daily calcium intake from both dietary and supplemental sources was approximately 1200 mg.
All Cause Mortality
	Odanacatib 50 mg Once Weekly		Placebo Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Odanacatib 50 mg Once Weekly		Placebo Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	24/146 (16.4%)		24/146 (16.4%)
Cardiac disorders
Angina pectoris	0/146 (0%)	0	1/146 (0.7%)	1
Angina unstable	1/146 (0.7%)	1	0/146 (0%)	0
Atrioventricular block second degree	1/146 (0.7%)	1	0/146 (0%)	0
Cardiac failure congestive	1/146 (0.7%)	1	0/146 (0%)	0
Coronary artery stenosis	1/146 (0.7%)	1	0/146 (0%)	0
Myocardial infarction	0/146 (0%)	0	2/146 (1.4%)	2
Myocardial ischaemia	0/146 (0%)	0	1/146 (0.7%)	1
Pericarditis	0/146 (0%)	0	1/146 (0.7%)	1
Sick sinus syndrome	1/146 (0.7%)	1	0/146 (0%)	0
Congenital, familial and genetic disorders
Hydrocele	1/146 (0.7%)	1	0/146 (0%)	0
Gastrointestinal disorders
Inguinal hernia	0/146 (0%)	0	1/146 (0.7%)	1
Melaena	0/146 (0%)	0	1/146 (0.7%)	1
Hepatobiliary disorders
Alcoholic liver disease	0/146 (0%)	0	1/146 (0.7%)	1
Cholecystitis acute	0/146 (0%)	0	1/146 (0.7%)	1
Cholelithiasis obstructive	0/146 (0%)	0	1/146 (0.7%)	1
Infections and infestations
Appendicitis	1/146 (0.7%)	1	0/146 (0%)	0
Arthritis infective	1/146 (0.7%)	1	0/146 (0%)	0
Bacteraemia	1/146 (0.7%)	1	0/146 (0%)	0
Diverticulitis	0/146 (0%)	0	1/146 (0.7%)	1
Erysipelas	1/146 (0.7%)	1	0/146 (0%)	0
Peritonitis	0/146 (0%)	0	1/146 (0.7%)	1
Retroperitoneal infection	0/146 (0%)	0	1/146 (0.7%)	1
Injury, poisoning and procedural complications
Clavicle fracture	2/146 (1.4%)	2	1/146 (0.7%)	1
Fibula fracture	1/146 (0.7%)	1	0/146 (0%)	0
Fractured sacrum	1/146 (0.7%)	1	0/146 (0%)	0
Heat exhaustion	1/146 (0.7%)	1	0/146 (0%)	0
Ilium fracture	0/146 (0%)	0	1/146 (0.7%)	1
Pelvic fracture	1/146 (0.7%)	1	0/146 (0%)	0
Postoperative hernia	0/146 (0%)	0	1/146 (0.7%)	1
Rib fracture	1/146 (0.7%)	1	1/146 (0.7%)	1
Tendon rupture	1/146 (0.7%)	1	0/146 (0%)	0
Tibia fracture	1/146 (0.7%)	1	0/146 (0%)	0
Investigations
Weight decreased	0/146 (0%)	0	1/146 (0.7%)	1
Musculoskeletal and connective tissue disorders
Back pain	1/146 (0.7%)	1	0/146 (0%)	0
Haemarthrosis	1/146 (0.7%)	1	0/146 (0%)	0
Intervertebral disc protrusion	2/146 (1.4%)	2	0/146 (0%)	0
Myopathy	1/146 (0.7%)	1	0/146 (0%)	0
Osteoarthritis	1/146 (0.7%)	1	1/146 (0.7%)	2
Tendonitis	1/146 (0.7%)	1	0/146 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Basal cell carcinoma	0/146 (0%)	0	1/146 (0.7%)	1
Benign gastric neoplasm	1/146 (0.7%)	1	0/146 (0%)	0
Bladder transitional cell carcinoma	0/146 (0%)	0	1/146 (0.7%)	1
Bronchial carcinoma	0/146 (0%)	0	1/146 (0.7%)	1
Chronic lymphocytic leukaemia	0/146 (0%)	0	1/146 (0.7%)	1
Haemangioma of bone	1/146 (0.7%)	1	0/146 (0%)	0
Lung neoplasm malignant	0/146 (0%)	0	1/146 (0.7%)	1
Malignant melanoma	1/146 (0.7%)	1	0/146 (0%)	0
Prostate cancer	0/146 (0%)	0	2/146 (1.4%)	2
Renal cell carcinoma	1/146 (0.7%)	1	0/146 (0%)	0
Small cell lung cancer	1/146 (0.7%)	1	0/146 (0%)	0
Squamous cell carcinoma	1/146 (0.7%)	1	1/146 (0.7%)	4
Nervous system disorders
Cerebral ischaemia	0/146 (0%)	0	1/146 (0.7%)	1
Syncope	1/146 (0.7%)	1	0/146 (0%)	0
Renal and urinary disorders
Calculus ureteric	0/146 (0%)	0	1/146 (0.7%)	1
Haematuria	1/146 (0.7%)	1	0/146 (0%)	0
Reproductive system and breast disorders
Benign prostatic hyperplasia	2/146 (1.4%)	2	0/146 (0%)	0
Respiratory, thoracic and mediastinal disorders
Respiratory failure	1/146 (0.7%)	1	0/146 (0%)	0
Vascular disorders
Hypertension	1/146 (0.7%)	1	1/146 (0.7%)	1
Hypotension	1/146 (0.7%)	2	0/146 (0%)	0
Other (Not Including Serious) Adverse Events
	Odanacatib 50 mg Once Weekly		Placebo Once Weekly
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	30/146 (20.5%)		44/146 (30.1%)
General disorders
Influenza like illness	4/146 (2.7%)	4	9/146 (6.2%)	11
Infections and infestations
Nasopharyngitis	14/146 (9.6%)	18	15/146 (10.3%)	18
Musculoskeletal and connective tissue disorders
Arthralgia	4/146 (2.7%)	4	10/146 (6.8%)	11
Back pain	9/146 (6.2%)	11	12/146 (8.2%)	15
Pain in extremity	3/146 (2.1%)	3	10/146 (6.8%)	12

Limitations/Caveats

[Not Specified]

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Certain Agreements

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

The SPONSOR must have the opportunity to review all proposed abstracts, manuscripts, or presentations regarding this study 60 days prior to submission for publication/presentation. Any information identified by the SPONSOR as confidential must be deleted prior to submission.