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Open Access 01-12-2024 | Breast Cancer | Update

Statistical analysis plan for the PRO B study: open-label, superiority randomised controlled trial of alarm-based patient-reported outcome monitoring in patients with metastatic breast cancer

Authors: Pimrapat Gebert, Maria Margarete Karsten, Anna Maria Hage, Adam David Dordevic, Ulrike Grittner

Published in: Trials | Issue 1/2024

Abstract

Background

With an increasing collection of patient-reported outcomes (PROs) to measure health-related quality of life (HRQoL) in oncological patients, there is still a lack of standardised strategies on how to interpret and use these data in patient care. Prior research has shown support for the use of digital PRO monitoring together with alarm systems to notify clinicians when the PRO values are deteriorating. This system has demonstrated advantages in improving HRQoL and increasing survival rates among oncology patients. Hence, we designed the PRO B study, a superiority multi-centre randomised controlled trial, to investigate the effects of alarm-based monitoring in metastatic breast cancer patients in Germany. The study protocol for the PRO B study was published in September 2021, and this manuscript describes a formal statistical analysis plan (SAP) for the PRO B study to improve the transparency and quality of this trial.

Methods and design

The trial aimed to recruit 1000 patients with metastatic breast cancer. However, as of the completion of recruitment on June 15, 2023, we have successfully enrolled 924 patients from 52 breast cancer centres. Patients were 1:1 stratified randomised to the intervention and control groups. App-based PRO questionnaires are sent weekly to the intervention group and every 3 months to the control group. Only patients in the intervention group trigger an alarm if their PRO scores deteriorate, and they are subsequently contacted by the local care team within 48 h. The primary outcome is the fatigue score at 6 months, and secondary outcomes are other HRQoL and overall survival. Evaluation of the superiority of the intervention will be done using a linear mixed model with random intercepts for study centres.

Conclusion

This detailed SAP defines the main components of the statistical analysis for the PRO B study to assist the statistician and prevent bias in selecting analysis and reporting findings. Version 1 of the SAP was finalised on January 18, 2024.

Trial registration

DRKS (German Clinical Trials Register) DRKS00024015. Registered on February 15, 2021.

Available only for authorised users

Basch E, Deal AM, Dueck AC, Scher HI, Kris MG, Hudis C, et al. Overall survival results of a trial assessing patient-reported outcomes for symptom monitoring during routine cancer treatment. JAMA. 2017;318:197–8. https://doi.org/10.1001/jama.2017.7156.CrossRefPubMedPubMedCentral

Basch E, Deal AM, Kris MG, Scher HI, Hudis CA, Sabbatini P, et al. Symptom monitoring with patient-reported outcomes during routine cancer treatment: a randomized controlled trial. J Clin Oncol. 2016;34:557–65. https://doi.org/10.1200/JCO.2015.63.0830.CrossRefPubMed

Denis F, Basch E, Septans AL, Bennouna J, Urban T, Dueck AC, et al. Two-year survival comparing web-based symptom monitoring vs routine surveillance following treatment for lung cancer. JAMA. 2019;321:306–7. https://doi.org/10.1001/jama.2018.18085.CrossRefPubMedPubMedCentral

Karsten MM, Kuhn F, Pross T, Blohmer JU, Hage AM, Fischer F, et al. PRO B: evaluating the effect of an alarm-based patient-reported outcome monitoring compared with usual care in metastatic breast cancer patients-study protocol for a randomised controlled trial. Trials. 2021;22:666. https://doi.org/10.1186/s13063-021-05642-6.CrossRefPubMedPubMedCentral

Gamble C, Krishan A, Stocken D, Lewis S, Juszczak E, Dore C, et al. Guidelines for the content of statistical analysis plans in clinical trials. JAMA. 2017;318:2337–43. https://doi.org/10.1001/jama.2017.18556.CrossRefPubMed

Aaronson NK, Ahmedzai S, Bergman B, Bullinger M, Cull A, Duez NJ, et al. The European Organization for Research and Treatment of Cancer QLQ-C30: a quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst. 1993;85:365–76. https://doi.org/10.1093/jnci/85.5.365.CrossRefPubMed

Petersen MA, Aaronson NK, Arraras JI, Chie WC, Conroy T, Costantini A, et al. The EORTC CAT Core-the computer adaptive version of the EORTC QLQ-C30 questionnaire. Eur J Cancer. 2018;100:8–16. https://doi.org/10.1016/j.ejca.2018.04.016.CrossRefPubMed

Fayers PM, Aaronson NK, Bjordal K, Groenvold M, Curran D, Bottomley A, et al. The EORTC QLQ-C30 scoring manual (3rd ed.). Brussels: European Organisation for Research and Treatment of Cancer; 2001.

Giesinger JM, Loth FLC, Aaronson NK, Arraras JI, Caocci G, Efficace F, et al. Thresholds for clinical importance were defined for the European Organisation for Research and Treatment of Cancer Computer Adaptive Testing Core-an adaptive measure of core quality of life domains in oncology clinical practice and research. J Clin Epidemiol. 2020;117:117–25. https://doi.org/10.1016/j.jclinepi.2019.09.028.CrossRefPubMed

10.

Cocks K, King MT, Velikova G, de Castro G, Martyn St-James M, Fayers PM, et al. Evidence-based guidelines for interpreting change scores for the European Organisation for the Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Eur J Cancer. 2012;48:1713–21. https://doi.org/10.1016/j.ejca.2012.02.059.CrossRefPubMed

11.

Cortes J, Hudgens S, Twelves C, Perez EA, Awada A, Yelle L, et al. Health-related quality of life in patients with locally advanced or metastatic breast cancer treated with eribulin mesylate or capecitabine in an open-label randomized phase 3 trial. Breast Cancer Res Treat. 2015;154:509–20. https://doi.org/10.1007/s10549-015-3633-7.CrossRefPubMedPubMedCentral

12.

UNESCO. International Standard Classification of Education: ISCED 1997. 2006.

13.

Stedman M, Doria-Rose P, Warren J, Klabunde C, Mariotto A. Comorbidity technical report: the impact of different SEER-Medicare claims-based comorbidity indexes on predicting non-cancer mortality for cancer patients. Bethesda: National Cancer Institute; 2017.

14.

Austin PC. A tutorial on multilevel survival analysis: methods, models and applications. Int Stat Rev. 2017;85:185–203. https://doi.org/10.1111/insr.12214.CrossRefPubMedPubMedCentral

15.

Maradit Kremers H, Devick KL, Larson DR, Lewallen DG, Berry DJ, Crowson CS. Competing Risk Analysis: what does it mean and when do we need it in orthopedics research? J Arthroplasty. 2021;36:3362–6. https://doi.org/10.1016/j.arth.2021.04.015.CrossRefPubMed

16.

Grobler AC, Lee KJ, Wong A, Currow DC, Braat S. Handling missing data and drop out in hospice/palliative care trials through the estimand framework. J Pain Symptom Manage. 2022;63:e431–9. https://doi.org/10.1016/j.jpainsymman.2021.12.022.CrossRefPubMed

17.

ICH. Integrated Addendum to ICH E6(R1); 2016. Guideline for Good Clinical Practice E6(R2). Available from: https://database.ich.org/sites/default/files/E6_R2_Addendum.pdf. Accessed 29 Nov 2023.

18.

Sullivan TR, White IR, Salter AB, Ryan P, Lee KJ. Should multiple imputation be the method of choice for handling missing data in randomized trials? Stat Methods Med Res. 2018;27:2610–26. https://doi.org/10.1177/0962280216683570.MathSciNetCrossRefPubMed

19.

Rubin DB. Multiple imputation for nonresponse in surveys. New York: John Wiley & Sons Inc; 1987.CrossRef

20.

Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from clinical assumptions to statistical analysis using pattern mixture models. Pharm Stat. 2013;12:337–47. https://doi.org/10.1002/pst.1549.CrossRefPubMed

21.

Bell ML, Floden L, Rabe BA, Hudgens S, Dhillon HM, Bray VJ, et al. Analytical approaches and estimands to take account of missing patient-reported data in longitudinal studies. Patient Relat Outcome Meas. 2019;10:129–40. https://doi.org/10.2147/PROM.S178963.CrossRefPubMedPubMedCentral

Title: Statistical analysis plan for the PRO B study: open-label, superiority randomised controlled trial of alarm-based patient-reported outcome monitoring in patients with metastatic breast cancer
Authors: Pimrapat Gebert
Maria Margarete Karsten
Anna Maria Hage
Adam David Dordevic
Ulrike Grittner
Publication date: 01-12-2024
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Fatigue
Published in: Trials / Issue 1/2024
Electronic ISSN: 1745-6215
DOI: https://doi.org/10.1186/s13063-024-08025-9

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Statistical analysis plan for the PRO B study: open-label, superiority randomised controlled trial of alarm-based patient-reported outcome monitoring in patients with metastatic breast cancer

Abstract

Background

Methods and design

Conclusion

Trial registration

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods and design

Conclusion

Trial registration

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