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Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women

Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women
Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women
Summary: this paper explores use of metrics that combine fracture outcomes that add power to phase 3 studies and provide a surrogate outcome for regulatory agencies. Introduction: the aim of this study was to develop an analytic framework that would combine information from all fracture outcomes (including radiographic vertebral fractures) in phase 3 studies to provide a metric for the assessment of treatment efficacy. Methods: data from the phase 3 study of denosumab were used as an exemplar comparing the effects of active intervention with placebo on the risk of all fractures associated with osteoporosis. Fracture outcomes were assigned utility weights drawn from the published literature and applied to age-specific health state values of the general population. For each fracture outcome in each arm of the study, cumulative disutility was computed to serve as the principal end point. The hypothesis tested was that treatment with denosumab results in a significant reduction in mean fracture-related disutility. Results: treatment with denosumab was associated with significantly lower utility loss compared with placebo. For patients treated with denosumab, mean utility loss was 42% less than with placebo (4.5 vs. 7.5 QALYs/1000 patient years, respectively, p < 0.001). Conclusions: Denosumab significantly decreased utility loss. The use of metrics that combine fracture outcomes may provide added power to phase 3 studies and provide a surrogate outcome for regulatory agencies.
Denosumab, Disutility, Fracture, Phase 3 study, Quality of life years
0937-941X
165-171
Kanis, J.A,
52c2c5a7-a17a-49dd-9b2a-30b5a1750a5d
Harvey, Nicholas
ce487fb4-d360-4aac-9d17-9466d6cba145
Lorentzon, M.
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Liu, Enwu
08027c15-9e71-44bb-9623-3081f5f6492d
Vandenput, Liesbeth
0910d143-4b58-4579-82b0-3810272f1814
McCloskey, E. V.
e968a69f-27b8-4568-987d-5d8dbbdff3fd
Johansson, Helena
04f12338-4dd1-437b-b9bc-e0884130c215
Kanis, J.A,
52c2c5a7-a17a-49dd-9b2a-30b5a1750a5d
Harvey, Nicholas
ce487fb4-d360-4aac-9d17-9466d6cba145
Lorentzon, M.
11692e10-5916-4bb5-86c5-3ff9ccd77af6
Liu, Enwu
08027c15-9e71-44bb-9623-3081f5f6492d
Vandenput, Liesbeth
0910d143-4b58-4579-82b0-3810272f1814
McCloskey, E. V.
e968a69f-27b8-4568-987d-5d8dbbdff3fd
Johansson, Helena
04f12338-4dd1-437b-b9bc-e0884130c215

Kanis, J.A,, Harvey, Nicholas, Lorentzon, M., Liu, Enwu, Vandenput, Liesbeth, McCloskey, E. V. and Johansson, Helena (2020) Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women. Osteoporosis International, 32 (1), 165-171. (doi:10.1007/s00198-020-05699-0).

Record type: Article

Abstract

Summary: this paper explores use of metrics that combine fracture outcomes that add power to phase 3 studies and provide a surrogate outcome for regulatory agencies. Introduction: the aim of this study was to develop an analytic framework that would combine information from all fracture outcomes (including radiographic vertebral fractures) in phase 3 studies to provide a metric for the assessment of treatment efficacy. Methods: data from the phase 3 study of denosumab were used as an exemplar comparing the effects of active intervention with placebo on the risk of all fractures associated with osteoporosis. Fracture outcomes were assigned utility weights drawn from the published literature and applied to age-specific health state values of the general population. For each fracture outcome in each arm of the study, cumulative disutility was computed to serve as the principal end point. The hypothesis tested was that treatment with denosumab results in a significant reduction in mean fracture-related disutility. Results: treatment with denosumab was associated with significantly lower utility loss compared with placebo. For patients treated with denosumab, mean utility loss was 42% less than with placebo (4.5 vs. 7.5 QALYs/1000 patient years, respectively, p < 0.001). Conclusions: Denosumab significantly decreased utility loss. The use of metrics that combine fracture outcomes may provide added power to phase 3 studies and provide a surrogate outcome for regulatory agencies.

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Dmab utilities v2 - Accepted Manuscript
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Accepted/In Press date: 17 September 2020
e-pub ahead of print date: 6 November 2020
Keywords: Denosumab, Disutility, Fracture, Phase 3 study, Quality of life years

Identifiers

Local EPrints ID: 445172
URI: http://eprints.soton.ac.uk/id/eprint/445172
ISSN: 0937-941X
PURE UUID: 40045f77-34d0-465e-96be-bf3c94268a44
ORCID for Nicholas Harvey: ORCID iD orcid.org/0000-0002-8194-2512

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Date deposited: 24 Nov 2020 17:32
Last modified: 26 Nov 2021 06:58

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Contributors

Author: J.A, Kanis
Author: Nicholas Harvey ORCID iD
Author: M. Lorentzon
Author: Enwu Liu
Author: Liesbeth Vandenput
Author: E. V. McCloskey
Author: Helena Johansson

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