Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial
Summary Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design...
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Published in | Osteoporosis international Vol. 26; no. 2; pp. 699 - 712 |
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Main Authors | , , , , , , , , , , , , |
Format | Journal Article |
Language | English |
Published |
London
Springer London
01.02.2015
Springer Nature B.V |
Subjects | |
Online Access | Get full text |
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Abstract | Summary
Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial.
Introduction
Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN.
Methods
The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D
3
(5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg.
Results
Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension.
Conclusions
This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. |
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AbstractList | Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction: Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods: The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score less than or equal to -2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score less than or equal to -1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D sub(3) (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results: Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions: This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. Summary Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Introduction Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. Methods The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤−2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤−1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D 3 (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Results Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. Conclusions This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone resorption and increases bone mineral density, with only a transient decrease in bone formation. We describe the background, design and participant characteristics for the phase 3 registration trial. Odanacatib (ODN) is a selective cathepsin K inhibitor being evaluated for the treatment of osteoporosis. In a phase 2 trial, ODN 50 mg once weekly reduced bone resorption while preserving bone formation and progressively increased BMD over 5 years. We describe the phase III Long-Term ODN Fracture Trial (LOFT), an event-driven, randomized, blinded placebo-controlled trial, with preplanned interim analyses to permit early termination if significant fracture risk reduction was demonstrated. An extension was planned, with participants remaining on their randomized treatment for up to 5 years, then transitioning to open-label ODN. The three primary outcomes were radiologically determined vertebral, hip, and clinical non-vertebral fractures. Secondary end points included clinical vertebral fractures, BMD, bone turnover markers, and safety and tolerability, including bone histology. Participants were women, 65 years or older, with a BMD T-score ≤-2.5 at the total hip (TH) or femoral neck (FN) or with a prior radiographic vertebral fracture and a T-score ≤-1.5 at the TH or FN. They were randomized to ODN or placebo tablets. All received weekly vitamin D^sub 3^ (5600 international units (IU)) and daily calcium supplements as needed to ensure a daily intake of approximately 1200 mg. Altogether, 16,713 participants were randomized at 387 centers. After a planned interim analysis, an independent data monitoring committee recommended that the study be stopped early due to robust efficacy and a favorable benefit/risk profile. Following the base study closeout, 8256 participants entered the study extension. This report details the background and study design of this fracture end point trial and describes the baseline characteristics of its participants. |
Author | Bone, H. G. Shih, W. J. Dempster, D. W. Verbruggen, N. Rybak-Feiglin, A. Greenspan, S. L. McClung, M. R. Papapoulos, S. Lombardi, A. Eisman, J. A. Nakamura, T. Leung, A. T. Santora, A. C. |
Author_xml | – sequence: 1 givenname: H. G. surname: Bone fullname: Bone, H. G. email: hgbone.md@att.net organization: Michigan Bone & Mineral Clinic, The Osteoporosis Center at St. Luke’s Hospital – sequence: 2 givenname: D. W. surname: Dempster fullname: Dempster, D. W. organization: Columbia University – sequence: 3 givenname: J. A. surname: Eisman fullname: Eisman, J. A. organization: Garvan Institute of Medical Research, University of Notre Dame Australia, St Vincent’s Hospital and UNSW Australia – sequence: 4 givenname: S. L. surname: Greenspan fullname: Greenspan, S. L. organization: University of Pittsburgh – sequence: 5 givenname: M. R. surname: McClung fullname: McClung, M. R. organization: Oregon Osteoporosis Center – sequence: 6 givenname: T. surname: Nakamura fullname: Nakamura, T. organization: University of Occupational and Environmental Health – sequence: 7 givenname: S. surname: Papapoulos fullname: Papapoulos, S. organization: Leiden University Medical Center – sequence: 8 givenname: W. J. surname: Shih fullname: Shih, W. J. organization: Robert Wood Johnson Medical School – sequence: 9 givenname: A. surname: Rybak-Feiglin fullname: Rybak-Feiglin, A. organization: Merck Sharp and Dohme Corp – sequence: 10 givenname: A. C. surname: Santora fullname: Santora, A. C. organization: Merck Sharp and Dohme Corp – sequence: 11 givenname: N. surname: Verbruggen fullname: Verbruggen, N. organization: Merck Sharp and Dohme Corp – sequence: 12 givenname: A. T. surname: Leung fullname: Leung, A. T. organization: Merck Sharp and Dohme Corp – sequence: 13 givenname: A. surname: Lombardi fullname: Lombardi, A. organization: Merck Sharp and Dohme Corp |
BackLink | https://www.ncbi.nlm.nih.gov/pubmed/25432773$$D View this record in MEDLINE/PubMed |
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Copyright | The Author(s) 2014 International Osteoporosis Foundation and National Osteoporosis Foundation 2015 |
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Keywords | Postmenopausal Osteoporosis Fracture Cathepsin K Odanacatib |
Language | English |
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PublicationSubtitle | With other metabolic bone diseases |
PublicationTitle | Osteoporosis international |
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Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly... Odanacatib is a cathepsin K inhibitor investigated for the treatment of postmenopausal osteoporosis. Phase 2 data indicate that 50 mg once weekly inhibits bone... |
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SubjectTerms | Aged Biphenyl Compounds - adverse effects Biphenyl Compounds - pharmacology Biphenyl Compounds - therapeutic use Bone Density - drug effects Bone Density Conservation Agents - adverse effects Bone Density Conservation Agents - pharmacology Bone Density Conservation Agents - therapeutic use Cathepsin K - antagonists & inhibitors Double-Blind Method Endocrinology Enzymes Female Femur Neck - physiopathology Fractures Hip Joint - physiopathology Humans Inhibitor drugs Medicine Medicine & Public Health Menopause Original Original Article Orthopedics Osteoporosis Osteoporosis, Postmenopausal - complications Osteoporosis, Postmenopausal - drug therapy Osteoporosis, Postmenopausal - physiopathology Osteoporotic Fractures - etiology Osteoporotic Fractures - physiopathology Osteoporotic Fractures - prevention & control Patient Selection Research Design Rheumatology Treatment Outcome |
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Title | Odanacatib for the treatment of postmenopausal osteoporosis: development history and design and participant characteristics of LOFT, the Long-Term Odanacatib Fracture Trial |
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