Supplementary appendix

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1 Supplementary appendix This appendix formed part of the original submission and has been peer reviewed. We post it as supplied by the authors. Supplement to: Langdahl BL, Libanati C, Crittenden DB, et al. (sclerostin monoclonal antibody) in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, openlabel, phase 3 trial. Lancet 2017; published online July S (17)

2 Supplementary appendix (sclerostin monoclonal antibody) in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial Bente L Langdahl, DMSc 1 ; Cesar Libanati, MD 2 ; Daria B Crittenden, MD 3 ; Michael A Bolognese, MD 4 ; Jacques P Brown, MD 5 ; Nadia S Daizadeh, PhD 3 ; Eva Dokoupilova, MD 6 ; Klaus Engelke, PhD 7 ; Joel S Finkelstein, MD 8 ; Harry K Genant, MD 9 ; Stefan Goemaere, MD 10 ; Lars Hyldstrup, MD 11 ; Esteban Jodar-Gimeno, MD 12 ; Tony M Keaveny, PhD 13 ; David Kendler, MD 14 ; Peter Lakatos, MD 15 ; Judy Maddox, DO 3 ; Jorge Malouf, MD 16 ; Fabio E Massari, MD 17 ; Jose Fernando Molina, MD 18 ; Maria Rosa Ulla, MD 19 ; Andreas Grauer, MD 3 1 Aarhus University Hospital, Aarhus, Denmark; 2 UCB Pharma, Brussels, Belgium; 3 Amgen Inc., Thousand Oaks, CA, USA; 4 Bethesda Health Research Center, Bethesda, MD, USA; 5 Laval University and CHU de Québec (CHUL) Research Centre, Quebec City, QC, Canada; 6 Medical Plus, Uherske Hradiste, Czech Republic; 7 BioClinica Inc., Hamburg, Germany and Institute of Medical Physics, University of Erlangen, Germany; 8 Department of Medicine, Massachusetts General Hospital, Boston, MA, USA; 9 Department of Radiology, University of California, San Francisco, CA, USA; 10 Ghent University Hospital, Gent, Belgium; 11 Hvidovre University Hospital, Hvidovre, Denmark; 12 Servicio de Endocrinología, Hospital Universitario Quirón Salud, Universidad Europea de Madrid, Madrid, Spain; 13 University of California at Berkeley, Berkeley, CA, USA; 14 Department of Medicine, University of British Columbia, Vancouver, BC, Canada; 15 Department of Medicine, Semmelweis University, Budapest, Hungary; 16 Universitat Autònoma de Barcelona, Barcelona, Spain; 17 Instituto de Investigaciones Metabólicas, Buenos Aires, Argentina; 18 Reumalab Centro Integral de Reumatología, Medellín, Colombia; 19 Instituto Latinoamericano de Investigaciones Médicas, Córdoba, Argentina Corresponding author: Professor Bente L Langdahl, DMSc Department of Endocrinology and Internal Medicine Aarhus University Hospital 8000 Aarhus C Denmark bente.langdahl@aarhus.rm.dk 1

3 Supplementary Methods Study protocol amendment summary The original study protocol was amended once. The amendment added assessments for formation of antiromosozumab antibodies at the month 1 and month 3 visits to allow a more comprehensive characterization of the anti-romosozumab antibody response. In addition, the eligibility criteria were modified to allow participation of a wider range of patients: the minimum age was lowered from 60 to 55 years and the protocol-mandated off-treatment times for exclusionary medications were revised. Retesting of serum calcium would be permitted within the screening window if the initial test indicated an elevated level of serum calcium within 1 1 the upper limit of normal set by the central laboratory to account for the imprecision of serum calcium laboratory measurements. The amendment added that a subset of up to 20 patients was to be recruited to undergo a transiliac bone biopsy at the month 12 visit to assess the effect of romosozumab treatment on parameters of bone histology and histomorphometry. The amendment also added detail to the justification for romosozumab treatment duration and dosing regimen. The expectations for serious adverse event reporting were redefined. Statistical analysis A two-step, step-down, fixed-sequential testing procedure was used for the primary and key secondary efficacy endpoints for the comparison of romosozumab with for multiplicity adjustment to maintain the overall significance level at Pre-specified testing procedure Step A: 1. Percent change in BMD by DXA at the total hip through month Percent change in BMD by DXA at the total hip at month 12 and percent change from in BMD by DXA at the total hip at month 6 Percent change in DXA BMD at the total hip through month 12 will be tested first. If statistical significance is declared, then percent change in BMD by DXA at the total hip at month 12 and percent change in BMD by DXA at the total hip at month 6 each will be tested, each at the 5% significance level. This procedure will ensure to control Type I error at 5% level. 1 If any of the three tests fail to declare statistical significance, inferential testing will not continue to step B. Step B: 1. Percent change in cortical BMD by QCT at the total hip at month 6 2. Percent change in cortical BMD by QCT at the total hip at month Percent change in integral BMD by QCT at the total hip at month 6 4. Percent change in integral BMD by QCT at the total hip at month Percent change in estimated strength by FEA at the total hip at month 6 6. Percent change in estimated strength by FEA at the total hip at month 12 In step B, the formal inferential testing can be performed for an endpoint only when the statistical significance is declared for the endpoint tested in the previous step. If the testing sequence is stopped at a particular step, the remaining endpoints in the testing sequence will be considered exploratory. References 1. Su T, Glimm E, Whitehead J, Branson M. An evaluation of methods for testing hypotheses relating to two endpoints in a single clinical trial. Pharm Stat. 2012; 11:

4 Appendix Table 1: at 6 and 12 months in secondary and additional efficacy variables (n=206) 6 Months 12 Months (n=209) (n=206) (n=209) BMD by DXA Total hip 2 3 (1 9, 2 7) < < ( 1 2, 0 4) (2 5, 3 4) < < ( 0 9, 0 0) Femoral neck 2 1 (1 6, 2 7) < < ( 1 6, 0 5) (2 6, 3 8) < < ( 0 8, 0 4) Lumbar spine 7 2 (6 6, 7 8) < < (2 9, 4 0) < (9 0, 10 5) < < (4 7, 6 1) < (n=176) (n=178) (n=176) (n=178) vbmd at the hip by QCT Integral 2 3 (1 9, 2 7) < < ( 1 1, 0 4) (2 9, 3 8) < < ( 0 7, 0 3) Cortical 0 7 (0 3, 1 1) < ( 3 1, 2 3) < (0 6, 1 6) < < ( 4 1, 3 1) < Trabecular 11 4 (7 2, 15 5) < (2 3, 10 6) (10 1, 21 1) < (4 4, 15 4) vbmc at the hip by QCT Integral 2 4 (2 1, 2 8) < < ( 1 1, 0 3) (3 1, 4 1) < < ( 0 4, 0 5) Cortical 1 7 (1 4, 2 1) < < ( 1 9, 1 1) < (2 5, 3 3) < < ( 1 7, 0 9) < Trabecular 10 9 (6 8, 15 0) < (1 8, 10 0) (10 3, 21 0) < (4 4, 15 2) Estimated hip strength by FEA 2 1 (1 6, 2 5) < < ( 1 5, 0 6) < (1 7, 3 2) < < ( 1 5, 0 1) n=the number of patients in the primary efficacy analysis set. Data are shown as least squares means (95% confidence interval). BMC=bone mineral content. BMD=bone mineral density. DXA=dual-energy x-ray absorptiometry. FEA=finite element analysis. QCT=quantitative computed tomography. v=volumetric. 3

5 Appendix Table 2: Absolute change at 12 months in vbmc at the hip by QCT n LS Mean (95% CI) n LS Mean (95% CI) vbmc at the hip by QCT, mg Integral (446 9, 577 8) ( 65 1, 66 7) < Cortical (249 5, 334 5) ( 176 6, 91 1) < Trabecular (117 5, 177 6) (102 8, 163 2) n=the number of patients in the primary efficacy analysis set. Data are shown as least squares (LS) means (95% confidence interval [CI]) based on a repeated measures model adjusting for treatment, serum CTX value, and BMC value. QCT=quantitative computed tomography. vbmc=volumetric bone mineral content. 4

6 Appendix Figure 1: STRUCTURE study design. ALN=alendronate. BP=bisphosphonate. QD=once daily. QM=once monthly. QW=once a week. SC=subcutaneous. 5