Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal
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ORIGINAL ARTICLE
Combining fracture outcomes in phase 3 trials of osteoporosis: an analysis of the effects of denosumab in postmenopausal women J. A. Kanis 1,2 & N. C. Harvey 3,4 & M. Lorentzon 5 & E. Liu 1 & L. Vandenput 1,6 & E. V. McCloskey 2,7 & H. Johansson 1,2 Received: 3 July 2020 / Accepted: 17 September 2020 # International Osteoporosis Foundation and National Osteoporosis Foundation 2020
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. Keywords Denosumab . Disutility . Fracture . Phase 3 study . Quality of life years
* J. A. Kanis [email protected] 1
Mary McKillop Institute for Health Research, Australian Catholic University, Melbourne, Australia
2
Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Beech Hill Road, Sheffield S10 2RX, UK
3
MRC Lifecourse Epidemiology Unit, University of Southampton, Southampton, UK
4
NIHR Southampton Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, UK
5
Geriatric Medicine, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
6
Department of Internal Medicine and Clinical Nutrition, Institute of Medicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
7
Mellanby Centre for bone research, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK
Introduction Current regulatory requirements for the development of treatments for osteoporosis in Europe and the USA demand that studies of efficacy in osteoporosis report vertebral and nonvertebral fracture outcomes separately [1,
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