Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan

Neill Kj Adhikari; Ruxandra Pinto; Andrew G Day; Marie-Hélène Masse; Julie Ménard; Sheila Sprague; Djillali Annane; Yaseen M Arabi; Marie-Claude Battista; Dian Cohen; Deborah J Cook; Gordon H Guyatt; Daren K Heyland; Salmaan Kanji; Shay P McGuinness; Rachael L Parke; Bharath Kumar Tirupakuzhi Vijayaraghavan; Emmanuel Charbonney; Michaël Chassé; Lorenzo Del Sorbo; Demetrios James Kutsogiannis; François Lauzier; Rémi Leblanc; David M Maslove; Sangeeta Mehta; Armand Mekontso Dessap; Tina S Mele; Bram Rochwerg; Oleksa G Rewa; Jason Shahin; Pawel Twardowski; Paul Jeffrey Young; François Lamontagne; LOVIT Investigators

doi:10.2196/36261

Lessening Organ Dysfunction With Vitamin C (LOVIT) Trial: Statistical Analysis Plan

JMIR Res Protoc. 2022 May 20;11(5):e36261. doi: 10.2196/36261.

Authors

Neill Kj Adhikari^#^{1

2}, Ruxandra Pinto¹, Andrew G Day^{3

4}, Marie-Hélène Masse⁵, Julie Ménard⁵, Sheila Sprague⁶, Djillali Annane^{7

8

9}, Yaseen M Arabi^{10

11

12}, Marie-Claude Battista¹³, Dian Cohen^{14

15}, Deborah J Cook^{16

17

18}, Gordon H Guyatt¹⁸, Daren K Heyland^{19

20

21}, Salmaan Kanji^{22

23}, Shay P McGuinness^{24

25

26}, Rachael L Parke^{24

25

26

27}, Bharath Kumar Tirupakuzhi Vijayaraghavan^{28

29}, Emmanuel Charbonney^{30

31}, Michaël Chassé^{30

32}, Lorenzo Del Sorbo^{2

33}, Demetrios James Kutsogiannis³⁴, François Lauzier^{35

36

37

38}, Rémi Leblanc^{39

40}, David M Maslove^{3

19

41}, Sangeeta Mehta^{2

42}, Armand Mekontso Dessap^{43

44

45}, Tina S Mele⁴⁶, Bram Rochwerg^{16

18}, Oleksa G Rewa³⁴, Jason Shahin^{47

48}, Pawel Twardowski⁴⁹, Paul Jeffrey Young^{25

26

50}, François Lamontagne^#^{5

13}; LOVIT Investigators⁵¹

Collaborators

LOVIT Investigators:
Patrick Archambault, Emilie P Belley-Côté, Marie-Josée Bériault, Ulrike Buehner, Troy Browne, Jean-Nicholas Dubé, Sandeep S Kohli, François Lellouche, Robert Martynoga, Andrew J E Seely, Geoffrey Shaw, Andrew Van Der Poll, Gordon Wood

Affiliations

¹ Department of Critical Care Medicine, Sunnybrook Health Sciences Centre, Toronto, ON, Canada.
² Interdepartmental Division of Critical Care Medicine, University of Toronto, Toronto, ON, Canada.
³ Kingston Health Sciences Centre, Kingston, ON, Canada.
⁴ Department of Public Health Sciences, Queen's University, Kingston, ON, Canada.
⁵ Research Centre of the Centre Hospitalier Universitaire de Sherbrooke, Sherbrooke, QC, Canada.
⁶ Division of Orthopaedic Surgery, Department of Surgery, McMaster University, Hamilton, ON, Canada.
⁷ Department of Intensive Care Medicine, Raymond-Poincaré Hospital (Assistance Publique - Hôpitaux de Paris [AP-HP]), Garches, France.
⁸ Institut National de la Santé et de la Recherche Médicale, Université Paris-Saclay Campus Université de Versailles Saint-Quentin-en-Yvelines, Versailles, France.
⁹ Fédération Hospitalo-Universitaire SEPSIS, Garches, France.
¹⁰ College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Riyadh, Saudi Arabia.
¹¹ King Abdullah International Medical Research Center, Riyadh, Saudi Arabia.
¹² Department of Intensive Care, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia.
¹³ Department of Medicine, Université de Sherbrooke, Sherbrooke, QC, Canada.
¹⁴ Bishop's University, Sherbroooke, QC, Canada.
¹⁵ Massawippi Valley Foundation, Ayer's Cliff, QC, Canada.
¹⁶ Department of Medicine, McMaster University, Hamilton, ON, Canada.
¹⁷ Department of Critical Care, St. Joseph's Healthcare Hamilton, Hamilton, ON, Canada.
¹⁸ Department of Health Research Methods, Evidence, and Impact, McMaster University, Hamilton, ON, Canada.
¹⁹ Department of Critical Care Medicine, Queen's University, Kingston, ON, Canada.
²⁰ Kingston General Health Research Institute, Kingston Health Sciences Centre, Kingston, ON, Canada.
²¹ Clinical Evaluation Research Unit, Kingston General Hospital, Kingston, ON, Canada.
²² The Ottawa Hospital Research Institute, Ottawa, ON, Canada.
²³ Department of Pharmacy, The Ottawa Hospital, Ottawa, ON, Canada.
²⁴ Cardiothoracic and Vascular Intensive Care Unit, Auckland City Hospital, Auckland, New Zealand.
²⁵ Medical Research Institute of New Zealand, Newtown, New Zealand.
²⁶ Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Australia.
²⁷ School of Nursing, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand.
²⁸ Department of Critical Care Medicine, Apollo Hospitals, Chennai, India.
²⁹ The George Institute for Global Health, New Delhi, India.
³⁰ Centre Hospitalier de l'Université de Montréal, Montréal, QC, Canada.
³¹ Centre de Recherche de l'Hôpital du Sacré-Coeur de Montréal, Montréal, QC, Canada.
³² Department of Medicine, Université de Montréal, Montréal, QC, Canada.
³³ Department of Medicine, University Health Network, Toronto, ON, Canada.
³⁴ Department of Critical Care Medicine, University of Alberta, Edmonton, AB, Canada.
³⁵ Department of Medicine, Université Laval, Québec, QC, Canada.
³⁶ Department of Anesthesiology and Critical Care, Université Laval, Québec, QC, Canada.
³⁷ Population Health and Optimal Health Practices Research Unit, Traumatology - Emergency - Critical Care Medicine, Centre Hospitalier Universitaire de Québec - Université Laval Research Center, Centre Hospitalier Universitaire de Québec - Université Laval, Québec, QC, Canada.
³⁸ Critical Care Medicine Service, Centre Hospitalier Universitaire de Québec - Université Laval, Quebec, QC, Canada.
³⁹ Department of Medicine, Centre Hospitalier Universitaire Dr Georges-L. Dumont, Moncton, NB, Canada.
⁴⁰ Division of Intensive Care, Centre Hospitalier Universitaire Dr Georges-L. Dumont, Moncton, NB, Canada.
⁴¹ Department of Medicine, Queen's University, Kingston, ON, Canada.
⁴² Sinai Health System, Toronto, ON, Canada.
⁴³ Service de Médecine Intensive Réanimation, Assistance Publique - Hôpitaux de Paris [AP-HP], Hôpitaux Universitaires Henri-Mondor, Créteil, France.
⁴⁴ Groupe de Recherche Clinique CARMAS (Cardiovascular and Respiratory Manifestations of Acute lung injury and Sepsis), Université de Paris Est Créteil, Créteil, France.
⁴⁵ Institut Mondor de Recherche Biomédicale, Institut National de la Santé et de la Recherche Médicale, Université Paris Est Créteil, Créteil, France.
⁴⁶ Department of Surgery, Schulich School of Medicine and Dentistry, Western University, London, ON, Canada.
⁴⁷ Department of Medicine, McGill University Health Centre, Montréal, QC, Canada.
⁴⁸ Department of Critical Care, McGill University Health Centre, Montréal, QC, Canada.
⁴⁹ Department of Surgical Sciences, University of Otago, Dunedin, New Zealand.
⁵⁰ Intensive Care Unit, Wellington Hospital, Newton, New Zealand.
⁵¹ See Acknowledgements, , .

^# Contributed equally.

PMID: 35420994
PMCID: PMC9166642
DOI: 10.2196/36261

Abstract

Background: The LOVIT (Lessening Organ Dysfunction with Vitamin C) trial is a blinded multicenter randomized clinical trial comparing high-dose intravenous vitamin C to placebo in patients admitted to the intensive care unit with proven or suspected infection as the main diagnosis and receiving a vasopressor.

Objective: We aim to describe a prespecified statistical analysis plan (SAP) for the LOVIT trial prior to unblinding and locking of the trial database.

Methods: The SAP was designed by the LOVIT principal investigators and statisticians, and approved by the steering committee and coinvestigators. The SAP defines the primary and secondary outcomes, and describes the planned primary, secondary, and subgroup analyses.

Results: The SAP includes a draft participant flow diagram, tables, and planned figures. The primary outcome is a composite of mortality and persistent organ dysfunction (receipt of mechanical ventilation, vasopressors, or new renal replacement therapy) at 28 days, where day 1 is the day of randomization. All analyses will use a frequentist statistical framework. The analysis of the primary outcome will estimate the risk ratio and 95% CI in a generalized linear mixed model with binomial distribution and log link, with site as a random effect. We will perform a secondary analysis adjusting for prespecified baseline clinical variables. Subgroup analyses will include age, sex, frailty, severity of illness, Sepsis-3 definition of septic shock, baseline ascorbic acid level, and COVID-19 status.

Conclusions: We have developed an SAP for the LOVIT trial and will adhere to it in the analysis phase.

International registered report identifier (irrid): DERR1-10.2196/36261.

Keywords: ascorbic acid; binomial distribution; critical care; health data; infection; intensive care; intensive care unit; intravenous; mortality; organ; organ dysfunction; patient; patient outcome; sepsis; statistical analysis; statistical framework; trial database; vasopressor; vitamin C.

©Neill KJ Adhikari, Ruxandra Pinto, Andrew G Day, Marie-Hélène Masse, Julie Ménard, Sheila Sprague, Djillali Annane, Yaseen M Arabi, Marie-Claude Battista, Dian Cohen, Deborah J Cook, Gordon H Guyatt, Daren K Heyland, Salmaan Kanji, Shay P McGuinness, Rachael L Parke, Bharath Kumar Tirupakuzhi Vijayaraghavan, Emmanuel Charbonney, Michaël Chassé, Lorenzo Del Sorbo, Demetrios James Kutsogiannis, François Lauzier, Rémi Leblanc, David M Maslove, Sangeeta Mehta, Armand Mekontso Dessap, Tina S Mele, Bram Rochwerg, Oleksa G Rewa, Jason Shahin, Pawel Twardowski, Paul Jeffrey Young, François Lamontagne, LOVIT Investigators. Originally published in JMIR Research Protocols (https://www.researchprotocols.org), 20.05.2022.