Osteoporosis
Conditions
Brief summary
This study will evaluate the safety and treatment effect of 50 mg odanacatib (MK-0822) with Vitamin D versus placebo with Vitamin D in postmenopausal women with low bone density. The primary efficacy hypothesis is that odanacatib will increase aBMD at the lumbar spine compared to placebo at 12 months.
Interventions
DRUGOdanacatib
Odanacatib 50 mg tablets, taken orally once weekly for 24 months.
DRUGPlacebo
Matching placebo tablets to odanacatib taken orally once weekly for 24 months.
DRUGVitamin D3
Vitamin D3 tablets (5600 IU) taken orally once weekly for 24 months.
Calcium supplement 500 mg tablet taken orally once daily (up to \ 1200 mg total) for 24 months.
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
FEMALE
Age
45 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
* Participant has been postmenopausal for 3 years * Participant has BMD t-score at the total hip, hip trochanter, femoral neck, or lumbar spine ≥ -1.5 but \> -3.5 * Participant has 2 hips that are evaluable by dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), e.g. contain no hardware from orthopedic procedures * Participant is ambulatory
Exclusion criteria
* Participant has had a previous hip fracture * Participant has had \>1 prior clinical vertebral fracture AND is a candidate for osteoporosis therapy * Participant has been treated with oral bisphosphonates, strontium, parathyroid hormone (PTH) or other agents with an effect on bone * Participant has had metabolic bone disorder other than osteoporosis * Participant has renal stones, Parkinson's disease, multiple sclerosis (MS) or active parathyroid disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD) | Baseline, 12 months | aBMD (g/cm\^2) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and mean BMD measurements from at least 3 evaluable lumbar spine vertebrae (L1-L4) were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal Analysis of Covariates (ANCOVA) model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively. |
| Percentage of Participants That Experienced an Adverse Event (AE) | Up to ~14 days post study end (up to ~24 months) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm. |
| Percentage of Participants That Discontinued Study Treatment Due to an AE | Up to ~14 days post study end (up to ~24 months) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (different from discontinuation of the study) due to an AE was reported for each treatment arm. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percent Change From Baseline in Hip Trochanter aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the hip trochanter. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the hip trochanter was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Total Radius aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the total radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Ultradistal Radius aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the ultradistal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the ultradistal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Distal Radius aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the one-third distal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the distal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline to Month 24 in Lumbar Spine aBMD | Baseline, 24 months | aBMD (g/cm\^2) was measured by DXA at the lumbar spine and mean BMD measurements from at least 3 evaluable vertebrae from L1 through L4 were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively. |
| Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Baseline, 12 months, 24 months | Trabecular vBMD at the lumbar spine (L2) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L2) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | Baseline, 12 months, 24 months | s-CTx is a biochemical marker index of bone resorption. s-CTx was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. S-CTx was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI. |
| Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | Baseline, 12 months, 24 months | s-P1NP is a biochemical marker index of bone formation. s-P1NP was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. s-P1NP was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI. |
| Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Baseline, 12 months, 24 months | Trabecular vBMD at the lumbar spine (L1) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L1) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Total Hip aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the total hip. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total hip was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
| Percent Change From Baseline in Femoral Neck aBMD | Baseline, 12 months, 24 months | aBMD (g/cm\^2) data was measured by DXA at the femoral neck (hip). All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the femoral neck was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. |
Participant flow
Pre-assignment details
214 participants who met inclusion criteria were randomized into either the Odanacatib 50 mg arm (N=109) or the Placebo arm (N=105).
Participants by arm
| Arm | Count |
|---|---|
| Odanacatib 50 mg Participants received 50 mg odanacatib and open-label 5600 IU vitamin D3 tablets once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg. | 109 |
| Placebo Participants received matching placebo to odanacatib and open-label 5600 IU vitamin D3 once weekly for 24 months. Participants also received 500 mg of open-label daily calcium supplement as needed to ensure a total daily calcium intake of 1200 mg. | 105 |
| Total | 214 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 11 | 5 |
| Overall Study | Lack of Efficacy | 0 | 1 |
| Overall Study | Lost to Follow-up | 3 | 1 |
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Withdrawal by Subject | 9 | 7 |
Baseline characteristics
| Characteristic | Odanacatib 50 mg | Placebo | Total |
|---|---|---|---|
| Age, Continuous | 63.9 years STANDARD_DEVIATION 7.3 | 64.0 years STANDARD_DEVIATION 6.2 | 64.0 years STANDARD_DEVIATION 6.8 |
| Sex: Female, Male Female | 109 Participants | 105 Participants | 214 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 67 / 109 | 68 / 105 |
| serious Total, serious adverse events | 13 / 109 | 16 / 105 |
Outcome results
Primary
Percentage of Participants That Discontinued Study Treatment Due to an AE
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that discontinued study treatment (different from discontinuation of the study) due to an AE was reported for each treatment arm.
Time frame: Up to ~14 days post study end (up to ~24 months)
Population: APaT population: all participants who took at least one dose of study medication, counted in the treatment group corresponding to the study treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Odanacatib 50 mg | Percentage of Participants That Discontinued Study Treatment Due to an AE | 10.1 percentage of participants |
| Placebo | Percentage of Participants That Discontinued Study Treatment Due to an AE | 5.7 percentage of participants |
Comparison: Estimated difference (versus Placebo) and CI were based on the Miettinen \& Nurminen method.95% CI: [-3.2, 12.3]
Primary
Percentage of Participants That Experienced an Adverse Event (AE)
An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of the SPONSOR's products, whether or not considered related to the use of the product. Any worsening (i.e., any clinically significant adverse change in frequency and/or intensity) of a preexisting condition which is temporally associated with the use of the SPONSOR's product was also an AE. The percentage of participants that experienced at least one AE was reported for each treatment arm.
Time frame: Up to ~14 days post study end (up to ~24 months)
Population: All-Participants-as-Treated (APaT) population: all participants who took at least one dose of study medication, counted in the treatment group corresponding to the study treatment they actually received.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Odanacatib 50 mg | Percentage of Participants That Experienced an Adverse Event (AE) | 82.6 percentage of participants |
| Placebo | Percentage of Participants That Experienced an Adverse Event (AE) | 84.8 percentage of participants |
Comparison: Estimated difference (versus Placebo) and CI were based on the Miettinen \& Nurminen method.95% CI: [-12.3, 7.9]
Primary
Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD)
aBMD (g/cm\^2) was measured by dual-energy X-ray absorptiometry (DXA) at the lumbar spine and mean BMD measurements from at least 3 evaluable lumbar spine vertebrae (L1-L4) were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal Analysis of Covariates (ANCOVA) model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.
Time frame: Baseline, 12 months
Population: Full-Analysis-Set (FAS) population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having Month 12 post-randomization lumbar spine aBMD endpoint data subsequent to at least one dose of study treatment, and having lumbar spine aBMD baseline (BL) data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD) | 3.63 percent change |
| Placebo | Percent Change From Baseline to Month 12 in Lumbar Spine Areal Bone Mineral Density (aBMD) | 0.14 percent change |
Comparison: A longitudinal ANCOVA was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% confidence interval (CI). The model, applied on all time points during treatment (Screening Visit \[BL\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. The weighted Least Squares (LS) mean is based on the described model. Difference in LS Means = Odancatib 50 mg minus Placebo.p-value: <0.00195% CI: [2.66, 4.32]Longitudinal Data Analysis (LDA) Model
Secondary
Percent Change From Baseline in Distal Radius aBMD
aBMD (g/cm\^2) data was measured by DXA at the one-third distal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the distal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization distal radius aBMD endpoint data subsequent to at least one dose of study treatment, and having distal radius aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Distal Radius aBMD | Month 24 (n=82, n=90) | -0.57 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Distal Radius aBMD | Month 12 (n=96, n=96) | -0.21 percent change |
| Placebo | Percent Change From Baseline in Distal Radius aBMD | Month 24 (n=82, n=90) | -1.79 percent change |
| Placebo | Percent Change From Baseline in Distal Radius aBMD | Month 12 (n=96, n=96) | -0.37 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: 0.69795% CI: [-0.63, 0.95]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: 0.01395% CI: [0.27, 2.18]LDA
Secondary
Percent Change From Baseline in Femoral Neck aBMD
aBMD (g/cm\^2) data was measured by DXA at the femoral neck (hip). All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the femoral neck was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization femoral neck aBMD endpoint data subsequent to at least one dose of study treatment, and having femoral neck aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Femoral Neck aBMD | Month 12 (n=96, n=97) | 1.03 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Femoral Neck aBMD | Month 24 (n=82, n=90) | 2.47 percent change |
| Placebo | Percent Change From Baseline in Femoral Neck aBMD | Month 12 (n=96, n=97) | -0.45 percent change |
| Placebo | Percent Change From Baseline in Femoral Neck aBMD | Month 24 (n=82, n=90) | -1.33 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: 0.00195% CI: [0.6, 2.35]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [2.69, 4.93]LDA
Secondary
Percent Change From Baseline in Hip Trochanter aBMD
aBMD (g/cm\^2) data was measured by DXA at the hip trochanter. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the hip trochanter was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization hip trochanter aBMD endpoint data subsequent to at least one dose of study treatment, and having hip trochanter aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Hip Trochanter aBMD | Month 12 (n=96, n=97) | 2.37 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Hip Trochanter aBMD | Month 24 (n=82, n=90) | 4.75 percent change |
| Placebo | Percent Change From Baseline in Hip Trochanter aBMD | Month 12 (n=96, n=97) | 0.18 percent change |
| Placebo | Percent Change From Baseline in Hip Trochanter aBMD | Month 24 (n=82, n=90) | -0.73 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [1.09, 3.29]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [4.08, 6.89]LDA
Secondary
Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level
s-CTx is a biochemical marker index of bone resorption. s-CTx was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. S-CTx was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.
Time frame: Baseline, 12 months, 24 months
Population: Per-Protocol (PP) population: All participants receiving at least one dose of study treatment and with available s-CTx data, excluding participants with important deviations from the protocol that may have substantially affected the results.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | Month 12 (n=89, n=87) | -53.33 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | Month 24 (n=74, n=78) | -42.56 percent change |
| Placebo | Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | Month 12 (n=89, n=87) | 0.70 percent change |
| Placebo | Percent Change From Baseline in Serum C-Terminal Telopeptides of Type 1 Collagen (s-CTx) Level | Month 24 (n=74, n=78) | 3.03 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-CTx (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline \[Randomization\], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [-64.81, -43.26]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-CTx (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline \[Randomization\], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [-62.22, -28.96]LDA
Secondary
Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level
s-P1NP is a biochemical marker index of bone formation. s-P1NP was measured via fasting blood draws at Baseline (Randomization), Month 6, Month 12, Month 18, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures. s-P1NP was analyzed using the log-transformed fraction from baseline using the per-protocol approach. Data were back-transformed for presentation and geometric LS mean percent change from baseline was reported with 95% CI.
Time frame: Baseline, 12 months, 24 months
Population: PP population: All participants receiving at least one dose of study treatment and with available s-P1NP data, excluding participants with important deviations from the protocol that may have substantially affected the results.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | Month 12 (n=90, n=88) | -28.32 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | Month 24 (n=76, n=80) | -11.06 percent change |
| Placebo | Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | Month 12 (n=90, n=88) | -2.97 percent change |
| Placebo | Percent Change From Baseline in Serum N-Terminal Propeptides of Type 1 Collagen (s-P1NP) Level | Month 24 (n=76, n=80) | -1.99 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-P1NP (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline \[Randomization\], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebo.p-value: <0.00195% CI: [-37.77, -12.92]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain geometric LS mean percent change from BL in s-P1NP (back-transformation of the log-transformed fraction from BL) and its 95% CI. The model, applied on all time points during treatment (Baseline \[Randomization\], Month 6, Month 12, Month 18, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebo.p-value: 0.22595% CI: [-23.69, 5.56]LDA
Secondary
Percent Change From Baseline in Total Hip aBMD
aBMD (g/cm\^2) data was measured by DXA at the total hip. All measurements utilized the same hip and at least 2 vertebrae for all time points. The left hip only was scanned. If the left hip was unevaluable, then the right hip was scanned. Once the appropriate leg was identified for scanning, it was used for all subsequent measurements. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total hip was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization total hip aBMD endpoint data subsequent to at least one dose of study treatment, and having total hip aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Total Hip aBMD | Month 12 (n=96, n=97) | 1.41 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Total Hip aBMD | Month 24 (n=82, n=90) | 2.43 percent change |
| Placebo | Percent Change From Baseline in Total Hip aBMD | Month 12 (n=96, n=97) | -0.16 percent change |
| Placebo | Percent Change From Baseline in Total Hip aBMD | Month 24 (n=82, n=90) | -0.89 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [0.88, 2.25]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [2.39, 4.26]LDA
Secondary
Percent Change From Baseline in Total Radius aBMD
aBMD (g/cm\^2) data was measured by DXA at the total radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the total radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization total radius aBMD endpoint data subsequent to at least one dose of study treatment, and having total radius aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Total Radius aBMD | Month 12 (n=96, n=96) | 0.01 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Total Radius aBMD | Month 24 (n=82, n=90) | -0.19 percent change |
| Placebo | Percent Change From Baseline in Total Radius aBMD | Month 12 (n=96, n=96) | -0.70 percent change |
| Placebo | Percent Change From Baseline in Total Radius aBMD | Month 24 (n=82, n=90) | -1.89 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: 0.0395% CI: [0.07, 1.35]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [0.97, 2.43]LDA
Secondary
Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2)
Trabecular vBMD at the lumbar spine (L2) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L2) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization QCT spine (L2) endpoint data subsequent to at least one dose of study treatment, and having QCT spine (L2) baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Month 12 (n=84, n=86) | 5.67 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Month 24 (n=73, n=79) | 5.97 percent change |
| Placebo | Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Month 12 (n=84, n=86) | -0.00 percent change |
| Placebo | Percent Change From Baseline in Trabecular vBMD at Central Section of Spine (L2) | Month 24 (n=73, n=79) | -3.41 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [3.77, 7.58]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [6.98, 11.77]LDA
Secondary
Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1)
Trabecular vBMD at the lumbar spine (L1) was measured by quantitative computed tomography (QCT). All QCT-derived vBMD measurements were evaluated centrally (and possibly locally) for bone and soft tissue abnormalities. Trabecular vBMD at the lumbar spine (L1) was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization QCT spine (L1) endpoint data subsequent to at least one dose of study treatment, and having QCT spine (L1) baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Month 12 (n=82, n=86) | 6.58 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Month 24 (n=72, n=79) | 6.44 percent change |
| Placebo | Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Month 12 (n=82, n=86) | -1.43 percent change |
| Placebo | Percent Change From Baseline in Trabecular Volumetric Bone Mineral Density (vBMD) at Central Section of Spine (L1) | Month 24 (n=72, n=79) | -5.02 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [6.03, 9.99]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [8.96, 13.97]LDA
Secondary
Percent Change From Baseline in Ultradistal Radius aBMD
aBMD (g/cm\^2) data was measured by DXA at the ultradistal radius (forearm). aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the ultradistal radius was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as secondary outcome measures.
Time frame: Baseline, 12 months, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having post-randomization ultradistal radius aBMD endpoint data subsequent to at least one dose of study treatment, and having ultradistal radius aBMD baseline data.
| Arm | Measure | Group | Value (LEAST_SQUARES_MEAN) |
|---|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline in Ultradistal Radius aBMD | Month 12 (n=96, n=96) | 0.98 percent change |
| Odanacatib 50 mg | Percent Change From Baseline in Ultradistal Radius aBMD | Month 24 (n=82, n=90) | 1.25 percent change |
| Placebo | Percent Change From Baseline in Ultradistal Radius aBMD | Month 12 (n=96, n=96) | -0.73 percent change |
| Placebo | Percent Change From Baseline in Ultradistal Radius aBMD | Month 24 (n=82, n=90) | -1.45 percent change |
Comparison: MONTH 12: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 12 = Odancatib 50 mg minus Placebop-value: 0.00195% CI: [0.69, 2.73]LDA
Comparison: MONTH 24: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and baseline value as covariate. The weighted LS mean is based on the described model. Difference in LS Means at Month 24 = Odancatib 50 mg minus Placebop-value: <0.00195% CI: [1.62, 3.78]LDA
Secondary
Percent Change From Baseline to Month 24 in Lumbar Spine aBMD
aBMD (g/cm\^2) was measured by DXA at the lumbar spine and mean BMD measurements from at least 3 evaluable vertebrae from L1 through L4 were used. If a vertebra was fractured at baseline or became fractured during the study, its BMD measurement was excluded from the analysis and the lumbar spine BMD was recalculated based on the three remaining vertebrae. aBMD data was centrally evaluated and all areal BMD measurements included a longitudinal BMD correction factor as determined by the quality control center. aBMD at the lumbar spine was assessed at the Screening visit (Baseline), Month 6, Month 12, and Month 24 for the repeated measures longitudinal ANCOVA model, with percent change from baseline at Months 12 and 24 pre-specified to be reported as primary and secondary outcome measures, respectively.
Time frame: Baseline, 24 months
Population: FAS population: a subset of All Randomized Participants with participants receiving at least one dose of study treatment, having Month 24 post-randomization lumbar spine aBMD endpoint data subsequent to at least one dose of study treatment, and having lumbar spine aBMD baseline data.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Odanacatib 50 mg | Percent Change From Baseline to Month 24 in Lumbar Spine aBMD | 5.02 percent change |
| Placebo | Percent Change From Baseline to Month 24 in Lumbar Spine aBMD | -0.38 percent change |
Comparison: A longitudinal ANCOVA model was used to obtain an estimate of the between-treatment difference in aBMD together with its 95% CI. The model, applied on all time points during treatment (Screening Visit \[Baseline\], Month 6, Month 12, Month 24), included treatment, region, time and interaction between treatment and time as fixed effects, and BL value as covariate. The weighted LS mean is based on the described model. Difference in LS Means = Odancatib 50 mg minus Placebo.p-value: <0.00195% CI: [4.36, 6.42]LDA