Successful Strategies and Areas of Improvement–Lessons Learned from Design and Conduction of a Randomized Placebo-Controlled Trial in Palliative Care, ‘Palliative-D’
Abstract
:1. Introduction
2. Methods
2.1. Study Design
2.1.1. Protocol
2.1.2. Participants
2.1.3. Sample Size
2.1.4. Outcome Measures
2.1.5. Data Collected at Screening
2.1.6. Name of Trial
3. Results
3.1. Study Conduct
3.1.1. Ethics Approval and Application to Medical Products Agency
3.1.2. Accrual
3.1.3. Attrition
3.1.4. Completeness of Data
3.2. Reporting
3.2.1. Statistical Challenges
3.2.2. Reporting
4. Discussion
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
- Aoun, S.M.; Nekolaichuk, C. Improving the evidence base in palliative care to inform practice and policy: Thinking outside the box. J. Pain Symptom Manag. 2014, 48, 1222–1235. [Google Scholar] [CrossRef]
- Engelbak Nielsen, Z.; Eriksson, S.; Schram Harsløf, L.B.; Petri, S.; Helgesson, G.; Mangset, M.; Godskesen, T.E. Are cancer patients better off if they participate in clinical trials? A mixed methods study. BMC Cancer 2020, 20, 401. [Google Scholar] [CrossRef] [PubMed]
- Bennett, M.I.; Davies, E.A.; Higginson, I.J. Delivering research in end-of-life care: Problems, pitfalls and future priorities. Palliat. Med. 2010, 24, 456–461. [Google Scholar] [CrossRef] [PubMed]
- Chen, E.K.; Riffin, C.; Reid, M.C.; Adelman, R.; Warmington, M.; Mehta, S.S.; Pillemer, K. Why is high-quality research on palliative care so hard to do? Barriers to improved research from a survey of palliative care researchers. J. Palliat. Med. 2014, 17, 782–787. [Google Scholar] [CrossRef] [Green Version]
- Kaasa, S.; Hjermstad, M.J.; Loge, J.H. Methodological and structural challenges in palliative care research: How have we fared in the last decades? Palliat. Med. 2006, 20, 727–734. [Google Scholar] [CrossRef]
- Barnes, H.; McDonald, J.; Smallwood, N.; Manser, R. Opioids for the palliation of refractory breathlessness in adults with advanced disease and terminal illness. Cochrane Database Syst. Rev. 2016, 3, Cd011008. [Google Scholar] [CrossRef] [Green Version]
- Mücke, M.; Mochamat; Cuhls, H.; Peuckmann-Post, V.; Minton, O.; Stone, P.; Radbruch, L. Pharmacological treatments for fatigue associated with palliative care: Executive summary of a Cochrane Collaboration systematic review. J. Cachex. Sarcopenia Muscle 2016, 7, 23–27. [Google Scholar] [CrossRef]
- Bouça-Machado, R.; Rosário, M.; Alarcão, J.; Correia-Guedes, L.; Abreu, D.; Ferreira, J.J. Clinical trials in palliative care: A systematic review of their methodological characteristics and of the quality of their reporting. BMC Palliat. Care 2017, 16, 10. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hui, D.; Parsons, H.A.; Damani, S.; Fulton, S.; Liu, J.; Evans, A.; De La Cruz, M.; Bruera, E. Quantity, design, and scope of the palliative oncology literature. Oncologist 2011, 16, 694–703. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Beller, E.M.; van Driel, M.L.; McGregor, L.; Truong, S.; Mitchell, G. Palliative pharmacological sedation for terminally ill adults. Cochrane Database Syst. Rev. 2015, 1, Cd010206. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Siemens, W.; Xander, C.; Meerpohl, J.J.; Buroh, S.; Antes, G.; Schwarzer, G.; Becker, G. Pharmacological interventions for pruritus in adult palliative care patients. Cochrane Database Syst. Rev. 2016, 11, Cd008320. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Helde Frankling, M.; Klasson, C.; Sandberg, C.; Nordström, M.; Warnqvist, A.; Bergqvist, J.; Bergman, P.; Björkhem-Bergman, L. ‘Palliative-D’-Vitamin D Supplementation to Palliative Cancer Patients: A Double Blind, Randomized Placebo-Controlled Multicenter Trial. Cancers 2021, 13, 3707. [Google Scholar] [CrossRef] [PubMed]
- Liu, P.T.; Stenger, S.; Li, H.; Wenzel, L.; Tan, B.H.; Krutzik, S.R.; Ochoa, M.T.; Schauber, J.; Wu, K.; Meinken, C.; et al. Toll-like receptor triggering of a vitamin D-mediated human antimicrobial response. Science 2006, 311, 1770–1773. [Google Scholar] [CrossRef]
- Wang, T.T.; Nestel, F.P.; Bourdeau, V.; Nagai, Y.; Wang, Q.; Liao, J.; Tavera-Mendoza, L.; Lin, R.; Hanrahan, J.W.; Mader, S.; et al. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J. Immunol. 2004, 173, 2909–2912. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Hewison, M. Antibacterial effects of vitamin D. Nat. Rev. Endocrinol. 2011, 7, 337–345. [Google Scholar] [CrossRef]
- Liu, X.; Nelson, A.; Wang, X.; Farid, M.; Gunji, Y.; Ikari, J.; Iwasawa, S.; Basma, H.; Feghali-Bostwick, C.; Rennard, S.I. Vitamin D modulates prostaglandin E2 synthesis and degradation in human lung fibroblasts. Am. J. Respir. Cell Mol. Biol. 2014, 50, 40–50. [Google Scholar]
- Helde-Frankling, M.; Bergqvist, J.; Klasson, C.; Nordstrom, M.; Hoijer, J.; Bergman, P.; Bjorkhem-Bergman, L. Vitamin D supplementation to palliative cancer patients: Protocol of a double-blind, randomised controlled trial ‘Palliative-D’. BMJ Support. Palliat. Care 2017, 7, 458–463. [Google Scholar] [CrossRef] [PubMed]
- Bergman, P.; Sperneder, S.; Hoijer, J.; Bergqvist, J.; Bjorkhem-Bergman, L. Low vitamin D levels are associated with higher opioid dose in palliative cancer patients--results from an observational study in Sweden. PLoS ONE 2015, 10, e0128223. [Google Scholar] [CrossRef] [Green Version]
- Helde-Frankling, M.; Hoijer, J.; Bergqvist, J.; Bjorkhem-Bergman, L. Vitamin D supplementation to palliative cancer patients shows positive effects on pain and infections-Results from a matched case-control study. PLoS ONE 2017, 12, e0184208. [Google Scholar] [CrossRef] [Green Version]
- Klasson, C.; Helde-Frankling, M.; Sandberg, C.; Nordström, M.; Lundh-Hagelin, C.; Björkhem-Bergman, L. Vitamin D and Fatigue in Palliative Cancer: A Cross-Sectional Study of Sex Difference in Baseline Data from the Palliative D Cohort. J. Palliat. Med. 2021, 24, 433–437. [Google Scholar] [CrossRef] [PubMed]
- Hussain, J.A.; Bland, M.; Langan, D.; Johnson, M.J.; Currow, D.C.; White, I.R. Quality of missing data reporting and handling in palliative care trials demonstrates that further development of the CONSORT statement is required: A systematic review. J. Clin. Epidemiol. 2017, 88, 81–91. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Isenberg, S.R.; Kavalieratos, D.; Chow, R.; Le, L.; Wegier, P.; Zimmermann, C. Quality versus risk of bias assessment of palliative care trials: Comparison of two tools. BMJ Support. Palliat. Care 2020. [Google Scholar] [CrossRef] [PubMed]
- Sigurdardottir, K.R.; Oldervoll, L.; Hjermstad, M.J.; Kaasa, S.; Knudsen, A.K.; Løhre, E.T.; Loge, J.H.; Haugen, D.F. How are palliative care cancer populations characterized in randomized controlled trials? A literature review. J. Pain Symptom Manag. 2014, 47, 906–914.e17. [Google Scholar] [CrossRef] [PubMed]
- Abernethy, A.P.; Aziz, N.M.; Basch, E.; Bull, J.; Cleeland, C.S.; Currow, D.C.; Fairclough, D.; Hanson, L.; Hauser, J.; Ko, D.; et al. A strategy to advance the evidence base in palliative medicine: Formation of a palliative care research cooperative group. J. Palliat. Med. 2010, 13, 1407–1413. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Currow, D.C.; Wheeler, J.L.; Glare, P.A.; Kaasa, S.; Abernethy, A.P. A framework for generalizability in palliative care. J. Pain Symptom Manag. 2009, 37, 373–386. [Google Scholar] [CrossRef]
- Preston, N.J.; Fayers, P.; Walters, S.J.; Pilling, M.; Grande, G.E.; Short, V.; Owen-Jones, E.; Evans, C.J.; Benalia, H.; Higginson, I.J.; et al. Recommendations for managing missing data, attrition and response shift in palliative and end-of-life care research: Part of the MORECare research method guidance on statistical issues. Palliat. Med. 2013, 27, 899–907. [Google Scholar] [CrossRef] [PubMed]
- Shelby-James, T.M.; Hardy, J.; Agar, M.; Yates, P.; Mitchell, G.; Sanderson, C.; Luckett, T.; Abernethy, A.P.; Currow, D.C. Designing and conducting randomized controlled trials in palliative care: A summary of discussions from the 2010 clinical research forum of the Australian Palliative Care Clinical Studies Collaborative. Palliat. Med. 2012, 26, 1042–1047. [Google Scholar] [CrossRef] [PubMed]
- Holm, M.; Alvariza, A.; Fürst, C.J.; Wengström, Y.; Årestedt, K.; Öhlen, J.; Goliath, I. Recruiting participants to a randomized controlled trial testing an intervention in palliative cancer care-The perspectives of health care professionals. Eur. J. Oncol. Nurs. Off. J. Eur. Oncol. Nurs. Soc. 2017, 31, 6–11. [Google Scholar] [CrossRef] [Green Version]
- Suzuki, K.; Ikari, T.; Matsunuma, R.; Matsuda, Y.; Matsumoto, Y.; Miwa, S.; Mori, M.; Yamaguchi, T.; Watanabe, H.; Tanaka, K. The Possibility of Conducting a Clinical Trial on Palliative Care: A Survey of Whether a Clinical Study on Cancer Dyspnea Is Acceptable to Cancer Patients and Their Relatives. J. Pain Symptom Manag. 2021. [Google Scholar] [CrossRef]
- Hanson, L.C.; Bull, J.; Wessell, K.; Massie, L.; Bennett, R.E.; Kutner, J.S.; Aziz, N.M.; Abernethy, A. Strategies to support recruitment of patients with life-limiting illness for research: The Palliative Care Research Cooperative Group. J. Pain Symptom Manag. 2014, 48, 1021–1030. [Google Scholar] [CrossRef]
- LeBlanc, T.W.; Lodato, J.E.; Currow, D.C.; Abernethy, A.P. Overcoming recruitment challenges in palliative care clinical trials. J. Oncol. Pract. 2013, 9, 277–282. [Google Scholar] [CrossRef] [Green Version]
- Mitchell, G.K.; Abernethy, A.P. A comparison of methodologies from two longitudinal community-based randomized controlled trials of similar interventions in palliative care: What worked and what did not? J. Palliat. Med. 2005, 8, 1226–1237. [Google Scholar] [CrossRef] [PubMed]
- Nguyen, H.Q.; McMullen, C.; Haupt, E.C.; Wang, S.E.; Werch, H.; Edwards, P.E.; Andres, G.M.; Reinke, L.; Mittman, B.S.; Shen, E.; et al. Findings and lessons learnt from early termination of a pragmatic comparative effectiveness trial of video consultations in home-based palliative care. BMJ Support. Palliat. Care 2020. [Google Scholar] [CrossRef] [PubMed]
- Stone, P.C.; Gwilliam, B.; Keeley, V.; Todd, C.; Kelly, L.C.; Barclay, S. Factors affecting recruitment to an observational multicentre palliative care study. BMJ Support. Palliat. Care 2013, 3, 318–323. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Sygna, K.; Johansen, S.; Ruland, C.M. Recruitment challenges in clinical research including cancer patients and their caregivers. A randomized controlled trial study and lessons learned. Trials 2015, 16, 428. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Nikles, J.; Mitchell, G.K.; Schluter, P.; Good, P.; Hardy, J.; Rowett, D.; Shelby-James, T.; Vohra, S.; Currow, D. Aggregating single patient (n-of-1) trials in populations where recruitment and retention was difficult: The case of palliative care. J. Clin. Epidemiol. 2011, 64, 471–480. [Google Scholar] [CrossRef] [PubMed]
- Heaney, R.P. Vitamin D--baseline status and effective dose. N. Engl. J. Med. 2012, 367, 77–78. [Google Scholar] [CrossRef] [Green Version]
- Hagen, N.A.; Wu, J.S.; Stiles, C.R. A proposed taxonomy of terms to guide the clinical trial recruitment process. J. Pain Symptom Manag. 2010, 40, 102–110. [Google Scholar] [CrossRef] [PubMed]
- Hui, D.; Arthur, J.; Dalal, S.; Bruera, E. Quality of the supportive and palliative oncology literature: A focused analysis on randomized controlled trials. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2012, 20, 1779–1785. [Google Scholar] [CrossRef] [PubMed]
- Evans, C.J.; Benalia, H.; Preston, N.J.; Grande, G.; Gysels, M.; Short, V.; Daveson, B.A.; Bausewein, C.; Todd, C.; Higginson, I.J. The selection and use of outcome measures in palliative and end-of-life care research: The MORECare International Consensus Workshop. J. Pain Symptom Manag. 2013, 46, 925–937. [Google Scholar] [CrossRef]
- Higginson, I.J.; Evans, C.J.; Grande, G.; Preston, N.; Morgan, M.; McCrone, P.; Lewis, P.; Fayers, P.; Harding, R.; Hotopf, M.; et al. Evaluating complex interventions in end of life care: The MORECare statement on good practice generated by a synthesis of transparent expert consultations and systematic reviews. BMC Med. 2013, 11, 111. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bausewein, C.; Daveson, B.A.; Currow, D.C.; Downing, J.; Deliens, L.; Radbruch, L.; Defilippi, K.; Lopes Ferreira, P.; Costantini, M.; Harding, R.; et al. EAPC White Paper on outcome measurement in palliative care: Improving practice, attaining outcomes and delivering quality services-Recommendations from the European Association for Palliative Care (EAPC) Task Force on Outcome Measurement. Palliat. Med. 2016, 30, 6–22. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Bruera, E.; Kuehn, N.; Miller, M.J.; Selmser, P.; Macmillan, K. The Edmonton Symptom Assessment System (ESAS): A simple method for the assessment of palliative care patients. J. Palliat. Care 1991, 7, 6–9. [Google Scholar] [CrossRef]
- Hui, D.; Bruera, E. The Edmonton Symptom Assessment System 25 Years Later: Past, Present, and Future Developments. J. Pain Symptom Manag. 2017, 53, 630–643. [Google Scholar] [CrossRef] [Green Version]
- Lundh Hagelin, C.; Klarare, A.; Furst, C.J. The applicability of the translated Edmonton Symptom Assessment System: Revised [ESAS-r] in Swedish palliative care. Acta Oncol. 2018, 57, 560–562. [Google Scholar] [CrossRef]
- Groenvold, M.; Petersen, M.A.; Aaronson, N.K.; Arraras, J.I.; Blazeby, J.M.; Bottomley, A.; Fayers, P.M.; de Graeff, A.; Hammerlid, E.; Kaasa, S.; et al. The development of the EORTC QLQ-C15-PAL: A shortened questionnaire for cancer patients in palliative care. Eur. J. Cancer 2006, 42, 55–64. [Google Scholar] [CrossRef]
- Lundh Hagelin, C.; Seiger, A.; Fürst, C.J. Quality of life in terminal care--with special reference to age, gender and marital status. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2006, 14, 320–328. [Google Scholar] [CrossRef] [PubMed]
- Michelson, H.; Bolund, C.; Nilsson, B.; Brandberg, Y. Health-related quality of life measured by the EORTC QLQ-C30--reference values from a large sample of Swedish population. Acta Oncol. 2000, 39, 477–484. [Google Scholar] [PubMed]
- Markman, J.D.; Rhyne, A.L.; Sasso, R.C.; Patel, A.A.; Hsu, W.K.; Fischgrund, J.S.; Edidin, A.A.; Vajkoczy, P. Association Between Opioid Use and Patient-Reported Outcomes in a Randomized Trial Evaluating Basivertebral Nerve Ablation for the Relief of Chronic Low Back Pain. Neurosurgery 2020, 86, 343–347. [Google Scholar] [CrossRef] [Green Version]
- Blatch-Jones, A.J.; Pek, W.; Kirkpatrick, E.; Ashton-Key, M. Role of feasibility and pilot studies in randomised controlled trials: A cross-sectional study. BMJ Open 2018, 8, e022233. [Google Scholar] [CrossRef] [Green Version]
- Cooper, C.L.; Whitehead, A.; Pottrill, E.; Julious, S.A.; Walters, S.J. Are pilot trials useful for predicting randomisation and attrition rates in definitive studies: A review of publicly funded trials. Clin. Trials 2018, 15, 189–196. [Google Scholar] [CrossRef]
- Bergman, P.; Norlin, A.C.; Hansen, S.; Rekha, R.S.; Agerberth, B.; Bjorkhem-Bergman, L.; Ekstrom, L.; Lindh, J.D.; Andersson, J. Vitamin D3 supplementation in patients with frequent respiratory tract infections: A randomised and double-blind intervention study. BMJ Open 2012, 2, e001663. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Björkhem-Bergman, L.; Missailidis, C.; Karlsson-Valik, J.; Tammelin, A.; Ekström, L.; Bottai, M.; Hammar, U.; Lindh, G.; Bergman, P. Vitamin D supplementation to persistent carriers of MRSA-a randomized and placebo-controlled clinical trial. Eur. J. Clin. Microbiol. Infect. Dis. Off. Publ. Eur. Soc. Clin. Microbiol. 2018, 37, 1735–1744. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Martineau, A.R.; Jolliffe, D.A.; Hooper, R.L.; Greenberg, L.; Aloia, J.F.; Bergman, P.; Dubnov-Raz, G.; Esposito, S.; Ganmaa, D.; Ginde, A.A.; et al. Vitamin D supplementation to prevent acute respiratory tract infections: Systematic review and meta-analysis of individual participant data. BMJ 2017, 356, i6583. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Norlin, A.C.; Hansen, S.; Wahren-Borgstrom, E.; Granert, C.; Bjorkhem-Bergman, L.; Bergman, P. Vitamin D3 Supplementation and Antibiotic Consumption-Results from a Prospective, Observational Study at an Immune-Deficiency Unit in Sweden. PLoS ONE 2016, 11, e0163451. [Google Scholar] [CrossRef]
- Van Mechelen, W.; Aertgeerts, B.; De Ceulaer, K.; Thoonsen, B.; Vermandere, M.; Warmenhoven, F.; Van Rijswijk, E.; De Lepeleire, J. Defining the palliative care patient: A systematic review. Palliat. Med. 2013, 27, 197–208. [Google Scholar] [CrossRef]
- Ohlén, J.; Wallengren Gustafsson, C.; Friberg, F. Making sense of receiving palliative treatment: Its significance to palliative cancer care communication and information provision. Cancer Nurs. 2013, 36, 265–273. [Google Scholar] [CrossRef] [PubMed]
- McIlfatrick, S.; Noble, H.; McCorry, N.K.; Roulston, A.; Hasson, F.; McLaughlin, D.; Johnston, G.; Rutherford, L.; Payne, C.; Kernohan, G.; et al. Exploring public awareness and perceptions of palliative care: A qualitative study. Palliat. Med. 2014, 28, 273–280. [Google Scholar] [CrossRef] [Green Version]
- Monga, V.; Maliske, S.M.; Kaleem, H.; Mott, S.L.; Zamba, G.K.D.; Milhem, M. Discrepancy between treatment goals documentation by oncologists and their understanding among cancer patients under active treatment with chemotherapy. Eur. J. Cancer Care 2019, 28, e12973. [Google Scholar] [CrossRef] [PubMed]
- Neugut, A.I.; Prigerson, H.G. Curative, Life-Extending, and Palliative Chemotherapy: New Outcomes Need New Names. Oncologist 2017, 22, 883–885. [Google Scholar] [CrossRef] [Green Version]
- Patell, R.; Einstein, D.; Miller, E.; Dodge, L.; Halleck, J.; Buss, M. Patient Perceptions of Treatment Benefit and Toxicity in Advanced Cancer: A Prospective Cross-Sectional Study. JCO Oncol. Pract. 2021, 17, e119–e129. [Google Scholar] [CrossRef] [PubMed]
- Weeks, J.C.; Catalano, P.J.; Cronin, A.; Finkelman, M.D.; Mack, J.W.; Keating, N.L.; Schrag, D. Patients’ expectations about effects of chemotherapy for advanced cancer. N. Engl. J. Med. 2012, 367, 1616–1625. [Google Scholar] [CrossRef] [PubMed] [Green Version]
- Maddocks, I. Issues in the conduct of therapeutic trials in palliative care: An Australian perspective. Drugs Aging 2002, 19, 495–502. [Google Scholar] [CrossRef]
- White, C.; Gilshenan, K.; Hardy, J. A survey of the views of palliative care healthcare professionals towards referring cancer patients to participate in randomized controlled trials in palliative care. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2008, 16, 1397–1405. [Google Scholar] [CrossRef]
- Bloomer, M.J.; Hutchinson, A.M.; Brooks, L.; Botti, M. Dying persons’ perspectives on, or experiences of, participating in research: An integrative review. Palliat. Med. 2018, 32, 851–860. [Google Scholar] [CrossRef] [Green Version]
- White, C.; Hardy, J. What do palliative care patients and their relatives think about research in palliative care?-a systematic review. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2010, 18, 905–911. [Google Scholar] [CrossRef]
- Walters, S.J.; Bonacho Dos Anjos Henriques-Cadby, I.; Bortolami, O.; Flight, L.; Hind, D.; Jacques, R.M.; Knox, C.; Nadin, B.; Rothwell, J.; Surtees, M.; et al. Recruitment and retention of participants in randomised controlled trials: A review of trials funded and published by the United Kingdom Health Technology Assessment Programme. BMJ Open 2017, 7, e015276. [Google Scholar] [CrossRef]
- Oriani, A.; Dunleavy, L.; Sharples, P.; Perez Algorta, G.; Preston, N.J. Are the MORECare guidelines on reporting of attrition in palliative care research populations appropriate? A systematic review and meta-analysis of randomised controlled trials. BMC Palliat. Care 2020, 19, 6. [Google Scholar] [CrossRef]
- Mandelli, S.; Riva, E.; Tettamanti, M.; Lucca, U.; Lombardi, D.; Miolo, G.; Spazzapan, S.; Marson, R. How palliative care professionals deal with predicting life expectancy at the end of life: Predictors and accuracy. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2021, 29, 2093–2103. [Google Scholar] [CrossRef]
- White, N.; Reid, F.; Harris, A.; Harries, P.; Stone, P. A Systematic Review of Predictions of Survival in Palliative Care: How Accurate Are Clinicians and Who Are the Experts? PLoS ONE 2016, 11, e0161407. [Google Scholar] [CrossRef] [Green Version]
- Baba, M.; Maeda, I.; Morita, T.; Inoue, S.; Ikenaga, M.; Matsumoto, Y.; Sekine, R.; Yamaguchi, T.; Hirohashi, T.; Tajima, T.; et al. Survival prediction for advanced cancer patients in the real world: A comparison of the Palliative Prognostic Score, Delirium-Palliative Prognostic Score, Palliative Prognostic Index and modified Prognosis in Palliative Care Study predictor model. Eur. J. Cancer 2015, 51, 1618–1629. [Google Scholar] [CrossRef]
- Hui, D.; Paiva, C.E.; Del Fabbro, E.G.; Steer, C.; Naberhuis, J.; van de Wetering, M.; Fernández-Ortega, P.; Morita, T.; Suh, S.Y.; Bruera, E.; et al. Prognostication in advanced cancer: Update and directions for future research. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2019, 27, 1973–1984. [Google Scholar] [CrossRef]
- Simmons, C.; McMillan, D.C.; Tuck, S.; Graham, C.; McKeown, A.; Bennett, M.; O’Neill, C.; Wilcock, A.; Usborne, C.; Fearon, K.C.; et al. “How Long Have I Got?”-A Prospective Cohort Study Comparing Validated Prognostic Factors for Use in Patients with Advanced Cancer. Oncologist 2019, 24, e960–e967. [Google Scholar] [CrossRef] [Green Version]
- Simmons, C.P.L.; McMillan, D.C.; McWilliams, K.; Sande, T.A.; Fearon, K.C.; Tuck, S.; Fallon, M.T.; Laird, B.J. Prognostic Tools in Patients With Advanced Cancer: A Systematic Review. J. Pain Symptom Manag. 2017, 53, 962–970.e910. [Google Scholar] [CrossRef] [Green Version]
- Manz, C.R.; Chen, J.; Liu, M.; Chivers, C.; Regli, S.H.; Braun, J.; Draugelis, M.; Hanson, C.W.; Shulman, L.N.; Schuchter, L.M.; et al. Validation of a Machine Learning Algorithm to Predict 180-Day Mortality for Outpatients With Cancer. JAMA Oncol. 2020, 6, 1723–1730. [Google Scholar] [CrossRef]
- Barclay, S.; Moran, E.; Boase, S.; Johnson, M.; Lovick, R.; Graffy, J.; White, P.L.; Deboys, B.; Harrison, K.; Swash, B. Primary palliative care research: Opportunities and challenges. BMJ Support. Palliat. Care 2019, 9, 468–472. [Google Scholar] [CrossRef]
- Currow, D.C.; Plummer, J.L.; Kutner, J.S.; Samsa, G.P.; Abernethy, A.P. Analyzing phase III studies in hospice/palliative care. a solution that sits between intention-to-treat and per protocol analyses: The palliative-modified ITT analysis. J. Pain Symptom Manag. 2012, 44, 595–603. [Google Scholar] [CrossRef]
- Grobler, A.C.; Lee, K. Intention-to-Treat Analyses for Randomized Controlled Trials in Hospice/Palliative Care Enhanced by Principled Methods to Handle Missing Data. J. Pain Symptom Manag. 2020, 60, e28–e29. [Google Scholar] [CrossRef]
- Huang, C.; Kochovska, S.; Currow, D.C. Letter in Response to Grobler AC, Lee K. Intention-To-Treat Analyses for Randomized Controlled Trials in Hospice/Palliative Care Enhanced by Principled Methods to Handle Missing Data. J. Pain Symptom Manag. 2020, 60, e30–e31. [Google Scholar] [CrossRef]
- Kochovska, S.; Huang, C.; Johnson, M.J.; Agar, M.R.; Fallon, M.T.; Kaasa, S.; Hussain, J.A.; Portenoy, R.K.; Higginson, I.J.; Currow, D.C. Intention-to-Treat Analyses for Randomized Controlled Trials in Hospice/Palliative Care: The Case for Analyses to be of People Exposed to the Intervention. J. Pain Symptom Manag. 2020, 59, 637–645. [Google Scholar] [CrossRef]
- Hui, D.; De La Cruz, M.; Mori, M.; Parsons, H.A.; Kwon, J.H.; Torres-Vigil, I.; Kim, S.H.; Dev, R.; Hutchins, R.; Liem, C.; et al. Concepts and definitions for “supportive care”, “best supportive care”, “palliative care”, and “hospice care” in the published literature, dictionaries, and textbooks. Support. Care Cancer Off. J. Multinatl. Assoc. Support. Care Cancer 2013, 21, 659–685. [Google Scholar] [CrossRef]
- Hui, D.; Mori, M.; Parsons, H.A.; Kim, S.H.; Li, Z.; Damani, S.; Bruera, E. The lack of standard definitions in the supportive and palliative oncology literature. J. Pain Symptom Manag. 2012, 43, 582–592. [Google Scholar] [CrossRef] [PubMed]
- LeBlanc, T.W.; Abernethy, A.P.; Currow, D.C.; Kutner, J.S. Considerations in reporting palliative care clinical trials: Standardizing information reported and authorship practices. Current Opin. Support. Palliat. Care 2012, 6, 494–499. [Google Scholar] [CrossRef] [PubMed]
- Schulz, K.F.; Altman, D.G.; Moher, D. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. BMJ 2010, 340, c332. [Google Scholar] [CrossRef]
- Unger, J.M.; Vaidya, R.; Hershman, D.L.; Minasian, L.M.; Fleury, M.E. Systematic Review and Meta-Analysis of the Magnitude of Structural, Clinical, and Physician and Patient Barriers to Cancer Clinical Trial Participation. J. Natl. Cancer Inst. 2019, 111, 245–255. [Google Scholar] [CrossRef]
- Murphy, M.; McCaughan, E.; Carson, M.A.; Donovan, M.; Wilson, R.H.; Fitzsimons, D. Nothing to lose: A grounded theory study of patients’ and healthcare professionals’ perspectives of being involved in the consent process for oncology trials with non-curative intent. BMC Palliat. Care 2020, 19, 166. [Google Scholar] [CrossRef] [PubMed]
- Hagen, N.A.; Stiles, C.R.; Biondo, P.D.; Cummings, G.G.; Fainsinger, R.L.; Moulin, D.E.; Pereira, J.L.; Spice, R. Establishing a multicentre clinical research network: Lessons learned. Curr. Oncol. 2011, 18, e243–e249. [Google Scholar] [CrossRef] [Green Version]
- Harding, R.; Higginson, I.J. PRISMA: A pan-European co-ordinating action to advance the science in end-of-life cancer care. Eur. J. Cancer 2010, 46, 1493–1501. [Google Scholar] [CrossRef]
- Lundström, S.; Axelsson, B.; Heedman, P.A.; Fransson, G.; Fürst, C.J. Developing a national quality register in end-of-life care: The Swedish experience. Palliat. Med. 2012, 26, 313–321. [Google Scholar] [CrossRef]
- Lundström, S.; Gyllenhammar, E.; Martinsson, U.; Strang, P. Together we can: Experiences from 7 years of cross-sectional studies in a Swedish palliative care clinical research network. Palliat. Med. 2010, 24, 261–266. [Google Scholar] [CrossRef]
- Henoch, I.; Carlander, I.; Holm, M.; James, I.; Sarenmalm, E.K.; Hagelin, C.L.; Lind, S.; Sandgren, A.; Öhlén, J. Palliative Care Research—A Systematic Review of foci, designs and methods of research conducted in Sweden between 2007 and 2012. Scand. J. Caring Sci. 2016, 30, 5–25. [Google Scholar] [CrossRef] [PubMed]
Aspect of Study Design/Conduct | Proposed Success Factors/Best Practice | Practical Application in “Palliative-D” | Comment |
---|---|---|---|
Protocol | Minimize burden on participants and clinical staff [27] | Outcome data retrieved from medical records Visits could be rescheduled +/−7 days | Very little missing data |
Align protocol with standard clinical practice [27] | Routinely collected outcome data (ESAS), outcome data collected at regular nurse visits | Very little missing data | |
Establish and monitor key performance indicators for recruitment and screening [27] | The study group continuously monitored this and changed study protocol to include more sites and to widen inclusion criteria | Improved accrual | |
Collect detailed demographic data to ensure generalizability [25] | We did not collect socioeconomic data | Reduces generalizability | |
Standardized assessment of physical performance status [25] | We did not use a validated instrument | Reduces generalizability | |
Participants | Keep inclusion and exclusion criteria as broad as possible [27] | Early change in inclusion criteria to allow for daily small intake of vitamin D | Improved accrual |
Ensure eligibility criteria can be applied uniformly across sites [27] | All sites in one region, uniform health care system | Ensured accrual | |
Sample size | Allow for attrition rates of 25–40% [27] | Sample size calculation on 25% attrition rate | Higher than expected attrition rate |
Outcome measurement | Assess primary endpoint data to occur as soon as clinical benefit is likely to occur [27] | 3-month follow-up due to slow onset of effects of vitamin D | High attrition rate due to deterioration and death |
Analysis plan | Modified ITT [77] | In our analysis we prespecified both ITT and PP analysis | We discussed using modified ITT with reviewers, but ended up with ITT with imputation and PP |
Study conduct | Provide support and coordination from a central office [27] | Karolinska Trial Alliance were contracted for help with initial study protocol and biobank | Valuable when working in a small team without administrative resources |
Promote routine screening of inclusion criteria [27] | We initially promoted screening of patients at time of enrolment in our teams | This did not work out; instead, a dedicated study team worked on accrual and retention | |
Convince clinicians of the importance of research for improving quality of care, regardless of results, maintain regular communication between sites [27] | Meetings before study start, regular newsletter at beginning of trial, regular team visits by study nurse, reporting of results after data analysis | Many team-members engaged in study procedures, positive attitude in all teams. |
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. |
© 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Share and Cite
Helde Frankling, M.; Klasson, C.; Björkhem-Bergman, L. Successful Strategies and Areas of Improvement–Lessons Learned from Design and Conduction of a Randomized Placebo-Controlled Trial in Palliative Care, ‘Palliative-D’. Life 2021, 11, 1233. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111233
Helde Frankling M, Klasson C, Björkhem-Bergman L. Successful Strategies and Areas of Improvement–Lessons Learned from Design and Conduction of a Randomized Placebo-Controlled Trial in Palliative Care, ‘Palliative-D’. Life. 2021; 11(11):1233. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111233
Chicago/Turabian StyleHelde Frankling, Maria, Caritha Klasson, and Linda Björkhem-Bergman. 2021. "Successful Strategies and Areas of Improvement–Lessons Learned from Design and Conduction of a Randomized Placebo-Controlled Trial in Palliative Care, ‘Palliative-D’" Life 11, no. 11: 1233. https://0-doi-org.brum.beds.ac.uk/10.3390/life11111233