A Study of MK-0822 in Postmenopausal Women With Osteoporosis to Assess Fracture Risk (MK-0822-018)

NCT00529373 | Terminated Phase 3 Results DMC FDA Drug

• 4 other identifiers: 0822-0182007_6101322382007-002693-66
• Study Type: interventional
• Target: 16,071
• Locations: 0 countries
• Sites: N/A

Brief Summary

The purpose of the event-driven base study is to determine the safety and efficacy, especially fracture risk reduction, of odanacatib in postmenopausal women diagnosed with osteoporosis. In a placebo-controlled extension of the base study, participants continued to receive the same blinded study medication for a total of up to 5 years of blinded study medication combined between the base study and the extension. After participants received 5 years of blinded study medication, they received open-label odanacatib through the end of the first extension. Participants were then invited to enroll in a second extension study in which they received open-label odanacatib for an additional 5 years. Two imaging substudies (PN032-Base/Extension and PN035) were conducted for participants in the MK-0822-018 Study. Additional safety information was collected for participants who discontinued from the base study or the blinded first extension in an observational follow-up study, MK-0822-083 (EudraCT number: 2007-002693-66) .

Conditions

Postmenopausal Osteoporosis

Outcome Measures

Primary Outcomes (16)

• Base Study: Time From Baseline to First Morphometrically-Assessed Vertebral Fracture

  Morphometric vertebral fractures were assessed by central adjudication on lumbar and thoracic spinal radiographs acquired at baseline and at Months 6, 12, and subsequent yearly time points. Incident fractures (i.e., occurring after baseline) in previously normal vertebral bodies and/or those occurring after baseline in previously fractured vertebral bodies (Genant semiquantitative \[SQ\] Grade 1-3) (T4 to L4) were confirmed by quantitative morphometric (QM) and either SQ or binary SQ (yes/no) methodologies. A time-to-event methodology was used to evaluate results: life-table estimates of the incidence proportion (cumulative incidence) of participants with at least one morphometric vertebral fracture were assessed at Months 6, 12, and subsequent yearly intervals; an interval-censored approach was then used to determine incidence rate (number of participants with a morphometric fracture per 100 person-years of follow-up).

  Up to approximately 60 months of observation

• Base Study: Time From Baseline to First Osteoporotic Clinical Hip Fracture (Adjudicated)

  Osteoporotic clinical hip fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Hip fractures were fractures of the proximal femur confirmed as being located in the hip (i.e., sub-region not specified; cervical, and intertrochanteric). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.

  Up to approximately 60 months of observation

• Base Study: Time From Baseline to First Osteoporotic Clinical Non-Vertebral Fracture (Adjudicated)

  Osteoporotic non-vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur or shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.

  Up to approximately 60 months of observation

• Base Study + First Extension: Time From Baseline to First Morphometrically-Assessed Vertebral Fracture

  Morphometric vertebral fractures were confirmed by central adjudication on lumbar and thoracic spinal radiographs acquired at baseline and at Months 6, 12, and subsequent yearly time points. Incident fractures (i.e., occurring after baseline) in previously normal vertebral bodies and/or those occurring after baseline in previously fractured vertebral bodies (Genant SQ Grade 1-3) (T4 to L4) were confirmed by QM and either SQ or binary SQ (yes/no) methodologies. A time-to-event methodology was used to evaluate results: life-table estimates of the incidence proportion (cumulative incidence) of participants with at least one morphometric vertebral fracture were assessed at Months 6, 12, and subsequent yearly intervals; an interval-censored approach was then used to determine incidence rate (number of participants with a morphometric fracture per 100 person-years of follow-up).

  Up to approximately 74 months of observation

• Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Hip Fracture (Adjudicated)

  Osteoporotic clinical hip fractures was confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Hip fractures were fractures of the proximal femur confirmed as being located in the hip (i.e., sub-region not specified; cervical, and intertrochanteric). Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.

  Up to approximately 74 months of observation

• Base Study + First Extension: Time From Baseline to First Osteoporotic Clinical Non-Vertebral Fracture (Adjudicated)

  Osteoporotic non-vertebral clinical fractures were confirmed by central adjudication using radiographic evidence on all symptomatic fractures reported as adverse experiences (excluding fractures of the fingers, toes, face, and skull). Non-vertebral fractures were assessed across multiple anatomical sites including clavicle, distal femur and shaft, fibula, hip, humerus, pelvis, radius, ribs, sacrum, tibia, ulna, and wrist. Osteoporotic (fragility) fractures did not include fractures with traumatic or pathological etiologies. A clinical fracture was defined as a fracture with clinical fracture-related symptoms (e.g., pain). A time-to-event methodology was used to evaluate results: the incidence rate of participants with fracture (number of participants with a fracture per 100 person-years of follow-up) is provided.

  Up to approximately 74 months of observation

• Base Study + First Extension: Rate of Adverse Events

  An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participants with adverse events (number of participants with an event per 100 person-years of follow-up) is provided.

  Up to approximately 74 months of observation

• Base Study + First Extension: Rate of Discontinuations From Study Treatment Due to an Adverse Event

  An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment. The incidence rate of participant discontinuations from treatment due to adverse events (number of participants with an event per 100 person-years of follow-up) is provided.

  Up to approximately 74 months of observation

• Base Study + First Extension + Second Extension: Percent Change From Baseline in Bone Mineral Density (BMD) Measurements of the Total Hip

  BMD was measured by dual-energy x-ray absorptiometry (DXA) at the total hip starting at screening, and at yearly intervals until the end of the study (second extension study) for all participants who entered the second extension study. Least squares (LS) means percent change in BMD from original baseline are provided through Month 108 (Year 9). At Months 96 (Year 8) and 108 (Year 9), approximately 3% or fewer participants in each treatment group had BMD data, and results at those time points should be viewed with caution. NOTE: The mean percent change in BMD from baseline in participants originally randomized to placebo includes BMD results obtained after those participants were switched to open-label odanacatib, which occurred at different times relative to their start of blinded study medication in the base study.

  Baseline and once yearly, up to approximately 108 months of observation

• Second Extension: Number of Participants Who Experienced an Adverse Event

  An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to approximately 34 months of observation

• Second Extension: Number of Participants Discontinuing Study Treatment Due to an Adverse Event

  An adverse event is defined as any untoward medical occurrence in a person or clinical investigation participant administered a pharmaceutical product and which does not necessarily have to have a causal relationship with this treatment.

  Up to approximately 34 months of observation

• Imaging Substudy PN032-Base: Percent Change From Baseline in Volumetric Bone Mineral Density (vBMD) at the Lumbar Spine Using Quantitative Computed Tomography

  Compartment-specific effects of osteoporosis were assessed by measuring trabecular vBMD at the lumbar spine (L1 total vertebral body) using quantitative computed tomography. The percent change from baseline at Month 24 (base study) was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).

  Baseline, Month 24

• Imaging Substudy PN032-Base + Extension: Percent Change From Baseline in vBMD at the Lumbar Spine Using Quantitative Computed Tomography

  Compartment-specific effects of osteoporosis were assessed by measuring trabecular vBMD at the lumbar spine (L1 total vertebral body) using quantitative computed tomography. The percent change from baseline at Month 60 (base study + extension study) was then assessed using a longitudinal data analysis model including terms for treatment, stratum (prior vertebral fracture \[yes/no\]) and interaction between treatment and time as fixed effects (LS means weighted for stratum size).

  Baseline, Month 60

• Sarcopenia Substudy PN035: Change From Baseline in Appendicular Lean Body Mass (aLBM)

  Sarcopenia is the age-related loss of skeletal muscle mass and associated loss of strength. Progression of sarcopenia was assessed using aLBM as measured by total body DXA. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).

  Baseline and once yearly up to 4 years

• Sarcopenia Substudy PN035: Change From Baseline in Short Physical Performance Battery (SPPB) Score

  The Short Physical Performance Battery (SPPB) Score is used to assess physical function in older persons. The SPPB consists of 3 types of physical activities: standing balance, gait speed, and chair rise. Component activities are timed and then reduced to a categorical 0 to 4 scale based on time achieved. A higher composite score (range 0 to 12) indicates an improved function level. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).

  Baseline and once yearly up to 4 years

• Sarcopenia Substudy PN035: Change From Baseline in Gait Speed

  Gait speed is a component of the Short Physical Performance Battery (SPPB) Score. Participants are asked to walk a distance of 4 meters at their normal pace. The test is performed 2 times, and the walk done in the shortest time is used for scoring. The activity is timed and then reduced to a categorical 0 to 4 scale based on time achieved. Higher scores indicate an improved function level. The change from baseline at yearly intervals was then assessed using a longitudinal data analysis model with terms for treatment, stratum (sarcopenia, non-sarcopenia), time and interaction between treatment and time as fixed effects (LS means weighted for stratum size).

  Baseline and once yearly up to 4 years.

Secondary Outcomes (61)

• Base Study: Rate of Adverse Events

  Up to approximately 60 months of observation

• Base Study: Rate of Discontinuation From Study Treatment Due to an Adverse Event

  Up to approximately 60 months of observation

• Base Study: Time From Baseline to First Osteoporotic Clinical Vertebral Fracture (Adjudicated)

  Up to approximately 60 months of observation

• Base Study: Yearly Rate of Height Loss

  Up to approximately 60 months of observation

• Base Study: Number of Participants With Height Loss of > 1 cm

  Baseline and once yearly, up to approximately 60 months of observation

Other Outcomes (12)

• Base Study + First Extension: Time to First Hospitalization for Unstable Angina Confirmed by TIMI Adjudication

  Up to approximately 74 months of observation

• Base Study + First Extension: Time to First Cardiovascular Death Confirmed by TIMI Adjudication

  Up to approximately 74 months of observation

• Base Study + First Extension: Time to First Fatal Myocardial Infarction Confirmed by TIMI Adjudication

  Up to approximately 74 months of observation

Study Arms (2)

Odanacatib

EXPERIMENTAL

Participants receive 50 mg of blinded odanacatib weekly over the course of the base study and first extension study (5 years total), followed by 50 mg of open-label odanacatib weekly for 5 years. Participants also receive Vitamin D3 and open-label supplemental calcium so that total daily calcium intake (from both dietary and supplemental sources) is approximately 1200 mg.

Drug: Odanacatib; Dietary Supplement: Vitamin D3; Dietary Supplement: Calcium carbonate

Placebo

PLACEBO COMPARATOR

Participants receive blinded placebo to 50 mg of odanacatib weekly over the course of the base study and first extension study (5 years total), followed by 50 mg of open-label odanacatib weekly for 5 years. Participants also receive Vitamin D3 and open-label supplemental calcium so that total daily calcium intake (from both dietary and supplemental sources) is approximately 1200 mg.

Drug: Placebo for Odanacatib; Dietary Supplement: Vitamin D3; Dietary Supplement: Calcium carbonate

Interventions

Odanacatib DRUG

50 mg tablet orally once weekly (OW)

Also known as: MK-0822

Odanacatib

Placebo for Odanacatib DRUG

50 mg tablet orally OW

Placebo

Vitamin D3 DIETARY_SUPPLEMENT

5600 IU orally OW

Odanacatib; Placebo

Calcium carbonate DIETARY_SUPPLEMENT

If needed. Total daily calcium intake (from both dietary and supplemental sources) will be approximately 1200 mg but not to exceed 1600 mg

Also known as: Calcium supplements

Odanacatib; Placebo

Eligibility Criteria

• Age: 65 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Older Adult (65+)

You may qualify if:

• Postmenopausal women (for at least 5 years) who are ≥65 years of age and have low bone mineral density
• Ambulatory (able to walk)

You may not qualify if:

• Must not be taking osteoporosis therapy or have a metabolic bone disorder other than osteoporosis
• Has or has had a hip fracture
• Currently participating in another drug study

Sponsors & Collaborators

• Merck Sharp & Dohme LLC: lead

Related Publications (5)

• Bone HG, Dempster DW, Eisman JA, Greenspan SL, McClung MR, Nakamura T, Papapoulos S, Shih WJ, Rybak-Feiglin A, Santora AC, Verbruggen N, Leung AT, Lombardi A. Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial. Osteoporos Int. 2015 Feb;26(2):699-712. doi: 10.1007/s00198-014-2944-6. Epub 2014 Nov 29.

  PMID: 25432773 BACKGROUND

• Duong LT, Clark S, Pickarski M, Giezek H, Cohn D, Massaad R, Stoch SA. Effects of odanacatib on bone-turnover markers in osteoporotic postmenopausal women: a post hoc analysis of the LOFT study. Osteoporos Int. 2022 Oct;33(10):2165-2175. doi: 10.1007/s00198-022-06406-x. Epub 2022 Jun 17.

  PMID: 35711006 DERIVED

• Papapoulos S, Bone H, Cosman F, Dempster DW, McClung MR, Nakamura T, Restrepo JFM, Bouxsein ML, Cohn D, de Papp A, Massaad R, Santora A. Incidence of Hip and Subtrochanteric/Femoral Shaft Fractures in Postmenopausal Women With Osteoporosis in the Phase 3 Long-Term Odanacatib Fracture Trial. J Bone Miner Res. 2021 Jul;36(7):1225-1234. doi: 10.1002/jbmr.4284. Epub 2021 Apr 27.

  PMID: 33724542 DERIVED

• Recker R, Dempster D, Langdahl B, Giezek H, Clark S, Ellis G, de Villiers T, Valter I, Zerbini CA, Cohn D, Santora A, Duong LT. Effects of Odanacatib on Bone Structure and Quality in Postmenopausal Women With Osteoporosis: 5-Year Data From the Phase 3 Long-Term Odanacatib Fracture Trial (LOFT) and its Extension. J Bone Miner Res. 2020 Jul;35(7):1289-1299. doi: 10.1002/jbmr.3994. Epub 2020 May 5.

  PMID: 32119749 DERIVED

• McClung MR, O'Donoghue ML, Papapoulos SE, Bone H, Langdahl B, Saag KG, Reid IR, Kiel DP, Cavallari I, Bonaca MP, Wiviott SD, de Villiers T, Ling X, Lippuner K, Nakamura T, Reginster JY, Rodriguez-Portales JA, Roux C, Zanchetta J, Zerbini CAF, Park JG, Im K, Cange A, Grip LT, Heyden N, DaSilva C, Cohn D, Massaad R, Scott BB, Verbruggen N, Gurner D, Miller DL, Blair ML, Polis AB, Stoch SA, Santora A, Lombardi A, Leung AT, Kaufman KD, Sabatine MS; LOFT Investigators. Odanacatib for the treatment of postmenopausal osteoporosis: results of the LOFT multicentre, randomised, double-blind, placebo-controlled trial and LOFT Extension study. Lancet Diabetes Endocrinol. 2019 Dec;7(12):899-911. doi: 10.1016/S2213-8587(19)30346-8. Epub 2019 Oct 31.

  PMID: 31676222 DERIVED

MeSH Terms

Conditions

Osteoporosis, Postmenopausal

Interventions

odanacatib; Cholecalciferol; Calcium Carbonate

Condition Hierarchy (Ancestors)

Osteoporosis; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases; Metabolic Diseases; Nutritional and Metabolic Diseases

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids; Calcium Compounds; Inorganic Chemicals; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Limitations and Caveats

The study was terminated early due to an observed increase in risk of stroke in Protocol MK-0822-018.

Results Point of Contact

• Title: Senior Vice President, Global Clinical Development,
• Organization: Merck Sharp & Dohme Corp.

ClinicalTrialsDisclosure@merck.com

1-800-672-6372

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 12, 2007
• First Posted: September 14, 2007
• Study Start: September 13, 2007
• Primary Completion: November 14, 2012
• Study Completion: February 1, 2017
• Last Updated: June 11, 2024
• Results First Posted: November 14, 2019

Record last verified: 2024-05

Data Sharing

• IPD Sharing: Will share