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Cognitive Outcomes in the Pragmatic Investigation of optimaL Oxygen Targets (CO-PILOT) trial: protocol and statistical analysis plan

Introduction Long-term cognitive impairment is one of the most common complications of critical illness among survivors who receive mechanical ventilation. Recommended oxygen targets during mechanical ventilation vary among international guidelines. Different oxygen targets during mechanical ventilation have the potential to alter long-term cognitive function due to cerebral hypoxemia or hyperoxemia. Whether higher, intermediate or lower SpO2 targets are associated with better cognitive function at 12-month follow-up is unknown. Methods and analysis The Pragmatic Investigation of optimaL Oxygen Targets (PILOT) trial is an ongoing pragmatic, cluster-randomised, cluster-crossover trial comparing the effect of a higher SpO2 target (target 98%, goal range 96%–100%), an intermediate SpO2 target (target 94%, goal range 92%–96%) and a lower SpO2 target (target 90%, goal range 88%–92%) on clinical outcomes in mechanically ventilated patients admitted to the medical intensive care unit at a single centre in the USA. For this ancillary study of long-term Cognitive Outcomes (CO-PILOT), survivors of critical illness who are in the PILOT trial and who do not meet exclusion criteria for CO-PILOT are approached for consent. The anticipated number of patients for whom assessment of long-term cognition will be performed in CO-PILOT is 612 patients over 36 months of enrolment. Cognitive, functional and quality of life assessments are assessed via telephone interview at approximately 12 months after enrolment in PILOT. The primary outcome of CO-PILOT is the telephone version of the Montreal Cognitive Assessment. A subset of patients will also complete a comprehensive neuropsychological telephone battery to better characterise the cognitive domains affected. Ethics and dissemination The CO-PILOT ancillary study was approved by the Vanderbilt Institutional Review Board. The results will be submitted for publication in a peer-reviewed journal and presented at one or more scientific conferences.

the achieved oxygen saturation tends to be above the intended target oxygen saturation in patients allocated to conservative oxygen target ranges. For example, the HOT-ICU study (Schjorring et al,Reference 22 in this paper) reported a median PaO2 of 93.3 mm Hg when they targeted 90mm ("higher oxygenation group"). This was slightly above their target. However, in their "lower oxygenation group", they had a target arterial oxygen tension of 60mm Hg but the median achieved PaO2 was greatly above this figure at 70.8mm Hg. Separation was achieved in that study but not as much as was intended. As the present study has three oxygen target ranges, separation will be more difficult to achieve, especially between the middle group and the other two groups. A modest difference in achieved oxygen saturation could be partially overcome if a study were to include very large numbers of patients but that will not be the case with the present study.
2. The exclusion criteria, consent methodology and partial blinding arrangements seem reasonable to me.
3. The main outcome measures in this protocol are neurophysiological tools which are outside my area of expertise. I note that the MOCA assessment is well validated in paper form for use in survivors of critical illness but the adoption for telephone use is less well validated the investigators have added some additional locally-derived questions. I would advise taking separate expert advice on these aspects of the study. 4. Expert statistical advice will also be required. The anticipated number of patients in each group is only about 200. The ICU-ROX study recruited 500 ventilated ICU patients in each group and did not show a difference in the main outcome which was ventilatorfree days to day 28. As the present study commenced recruitment in July 2019 and will finish recruitment in August of this year, the current recruitment figure will be very close to the final figure which is likely to be known as a provisional figure by the time this paper goes to press. I note that the journal's rules allow the submission of some baseline data for on-going studies, This information (number of patients recruited) should be entered in the paper because under-recruitment from the rather low intended recruitment target would present major obstacles to achieving a clear outcome.
5. The secondary outcomes seem reasonable to me but I would ask the statistical expert to advise on possible confounding by multiple analyses.

REVIEWER
Williams, Norman University College London, UCL Division of Surgery & Interventional Science

GENERAL COMMENTS
This manuscript describes the protcol for a sub-study of an ongoing RCT. The paper is well-written and this reviewer has no criticisms or suggestions for change. Authors' Response #1: We thank the reviewer for this suggestion. We agree and have highlighted the impact of not being able to measure premorbid cognitive function further in our revisions as outlined below.

Strengths and Limitations of this Study
• The broad inclusion criteria will increase the generalizability of the findings, and the sample size will allow examination of both global cognition and individual cognitive domains commonly impacted by critical illness. • The anticipated sample size and study design will allow for the assessment of not only global cognition, but also individual cognitive domains that can be impacted by critical illness. • The study utilizes an alteration of the process for informed consent that allows for consent to be obtained over the phone. • Enrollment in the primary study is limited to one U.S. academic medical center and enrollment in this ancillary study of long-term outcomes is limited to those patients able to complete follow-up. • The design of the study does not allow assessment of pre-illness cognition other than collecting data on pre-existing diagnoses of dementia and comorbidities from the electronic health record.

Page 11, Statistical Analysis and Reporting, Paragraph 2 (Subsection -Main Analysis of Primary Outcome): "
In the primary analysis, we will use generalized estimating equations with T-MOCA as the dependent variable, study period as the cluster, and trial group assignment (higher, lower, and intermediate SpO2 target) as the independent variable and the following pre-specified baseline covariates: age, sex, race/ethnicity, years of education, pre-illness dementia diagnosis, comorbidities (chronic obstructive pulmonary disease -COPD, congestive heart failure -CHF, coronary artery disease -CAD, end-stage renal disease -ESRD), cardiac arrest, and baseline nonrespiratory Sequential Organ Failure Assessment (SOFA) score. The parent PILOT study did not collect baseline cognitive status, and the CO-PILOT study participants are contacted for participation one year after critical illness, making it difficult to accurately characterize preillness cognition."

Response to Reviewer 2
Reviewer 2 General Comments: "The research question that is addressed by this protocol is an important one, given that poor neurological outcomes are common amongst survivors of critical illness, especially those who are mechanically ventilated. Overall, my impression is that this is a welldesigned study which will add to the body of knowledge in this important area of practice and the trial results could impact on decisions that are made in every intensive care unit in the world on a daily basis. This study commenced recruitment in 2019 and will compete patient recruitment in August 2022. For that reason, there is no option to modify any of the oxygen-related aspects of the study design which fall within my area of expertise in response to reviewer comments. However, the planned analysis of long-term cognitive outcomes could be modified if the statistical reviewer were to make significant suggestions." Authors' Response: We thank the reviewer for their positive feedback on our study and protocol manuscript.
Reviewer 2, Comment #1: "1. The results of this study will depend critically on whether clear separation is achieved between the oxygen saturation levels that are measured during the three treatment arms of the study. It has been observed in many studies of targeted oxygen therapy that the achieved oxygen saturation tends to be above the intended target oxygen saturation in patients allocated to conservative oxygen target ranges. For example, the HOT-ICU study (Schjorring et al, Reference 22 in this paper) reported a median PaO2 of 93.3 mm Hg when they targeted 90mm ("higher oxygenation group"). This was slightly above their target. However, in their "lower oxygenation group", they had a target arterial oxygen tension of 60mm Hg but the median achieved PaO2 was greatly above this figure at 70.8mm Hg. Separation was achieved in that study but not as much as was intended. As the present study has three oxygen target ranges, separation will be more difficult to achieve, especially between the middle group and the other two groups. A modest difference in achieved oxygen saturation could be partially overcome if a study were to include very large numbers of patients but that will not be the case with the present study." Authors' Response #1: We thank the reviewer for raising this important point. We agree that achieving adequate separation between groups is vital for assessing outcomes in both the parent study and in our ancillary CO-PILOT study presented in this protocol manuscript. We have completed the parent PILOT study analysis, and that manuscript is currently under review for publication. We anticipate that detailed information regarding the meaningful separation between groups from the PILOT parent trial will be available around the same time as this protocol manuscript (if accepted) and prior to publication of the results manuscript of the CO-PILOT study described in this protocol paper. This will allow readers to interpret both this protocol paper and the findings from future CO-PILOT results paper in the context of the reported separation between groups in the parent PILOT trial.
Reviewer 2, Comment #2: "2. The exclusion criteria, consent methodology and partial blinding arrangements seem reasonable to me." Authors' Response #2: We thank the reviewer for their positive feedback on our study design.
Reviewer 2, Comment #3: "3. The main outcome measures in this protocol are neuro-physiological tools which are outside my area of expertise. I note that the MOCA assessment is well validated in paper form for use in survivors of critical illness but the adoption for telephone use is less well validated the investigators have added some additional locally-derived questions. I would advise taking separate expert advice on these aspects of the study." Authors' Response #3: We thank the reviewer for their helpful feedback on the primary outcome, the telephone MoCA or T-MoCA, and we agree that this should be clarified further in the manuscript. The MoCA is a well-validated tool in survivors of critical illness, and the T-MoCA has been validated against the MoCA and found to perform well in multiple clinical cohorts (PMIDs: 34106473, 23138443, 34050916, 25590458, 29042492). Additionally, the T-MoCA is identical in form to the MoCA-Blind (Melikyan ZA, et al. Aging Clin Exp Res 2021;33(12):3303-11. PMID: 34050916), which is a recommended assessment tool in the Core Outcome Set for long-term outcomes studies in acute respiratory failure survivors completing follow-up remotely (Needham DM, et al. Am J Respir Crit Care Med. 2017;196(9):1122-1130. PMID: 28537429). We have expanded our discussion of the primary outcome to highlight these points and included the above references. Additionally, we expanded our discussion of our secondary cognitive outcome battery to highlight that the additional cognitive testing used in our study are derived from validated cognitive assessments and developed with expert advice from a trained neuropsychologist and cognitive outcomes researcher who has extensive experience in evaluating cognition after critical illness (PMID: 24088092, 33819472, 33528922, 32869075, 30346242). These manuscript revisions are outlined below.
Manuscript Revisions: Page 10, Methods and Analysis, Paragraph 12 (Subsection -Outcomes): "In January 1, 2020, we received additional funding (R21AG063126) to expand the neuropsychological battery to provide a more detailed assessment of executive function, attention, immediate and short-term memory, language, and abstraction (Table 1), allowing for additional testing from that point forward in the study. Cognitive domains such as executive function and attention are commonly impaired in survivors of critical illness [27]. A battery of additional validated cognitive assessments measuring individual cognitive domains (Table 1)  Reviewer 2, Comment #4: "4. Expert statistical advice will also be required. The anticipated number of patients in each group is only about 200. The ICU-ROX study recruited 500 ventilated ICU patients in each group and did not show a difference in the main outcome which was ventilator-free days to day 28. As the present study commenced recruitment in July 2019 and will finish recruitment in August of this year, the current recruitment figure will be very close to the final figure which is likely to be known as a provisional figure by the time this paper goes to press. I note that the journal's rules allow the submission of some baseline data for on-going studies, This information (number of patients recruited) should be entered in the paper because under-recruitment from the rather low intended recruitment target would present major obstacles to achieving a clear outcome."