Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation-A protocol for a randomized controlled pilot study.

BACKGROUND: Coronavirus disease 2019 (COVID-19), caused by the virus SARS-CoV-2, is spreading rapidly across the globe, with little proven effective therapy. Fever is seen in most cases of COVID-19, at least at the initial stages of illness. Although fever is typically treated (with antipyretics or directly with ice or other mechanical means), increasing data suggest that fever is a protective adaptive response that facilitates recovery from infectious illness.
OBJECTIVE: To describe a randomized controlled pilot study of core warming patients with COVID-19 undergoing mechanical ventilation.
METHODS: This prospective single-site randomized controlled pilot study will enroll 20 patients undergoing mechanical ventilation for respiratory failure due to COVID-19. Patients will be randomized 1:1 to standard-of-care or to receive core warming via an esophageal heat exchanger commonly utilized in critical care and surgical patients. The primary outcome is patient viral load measured by lower respiratory tract sample. Secondary outcomes include severity of acute respiratory distress syndrome (as measured by PaO2/FiO2 ratio) 24, 48, and 72 hours after initiation of treatment, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality.
RESULTS: Resulting data will provide effect size estimates to guide a definitive multi-center randomized clinical trial. ClinicalTrials.gov registration number: NCT04426344.
CONCLUSIONS: With growing data to support clinical benefits of elevated temperature in infectious illness, this study will provide data to guide further understanding of the role of active temperature management in COVID-19 treatment and provide effect size estimates to power larger studies.

RCT Entities:   Population Interventions Outcomes

Introduction

Traditionally, fever has been treated because its metabolic costs were felt to outweigh its potential physiologic benefit in an already stressed host [1]. However, increasing data suggest that fever may be a protective adaptive response that should be allowed to run its course under most circumstances [2,3]. Higher early fever is associated with a lower risk of death among patients with an ICU admission diagnosis of infection [4,5]. Fever may enhance immune-cell function [6,7], inhibit pathogen growth [8-10], and increase the activity of antimicrobial drugs [11]. Fever potentially benefits infected patients via multiple mechanisms; in vitro and animal studies have shown that elevated temperatures augment immune function, increase production of protective heat shock proteins, directly inhibit microorganism growth, reduce viral replication, and enhance antibiotic effectiveness [3,12]. More rapid recoveries are observed from chickenpox [13], malaria [14], and rhinovirus [15] infections with avoidance of antipyretic medication, and many innate and adaptive immunological processes are accelerated by fever [16-18].

Randomized controlled trials have consistently failed to find benefits to treating fever of infectious etiology [16,19-25]. Reducing patient temperature to below normal in sepsis likewise has been found to be of no benefit, or harmful [26,27]. On the other hand, warming appears to have substantial benefits in sepsis. Multiple aspects of both humoral and cellular immunity (including antibody production, T lymphocyte trafficking, T cell adhesion and migration, heat shock protein 90 (Hsp90)-induced α4 integrin activation and signaling, and macrophage function) are boosted by elevated temperature [28]. A retrospective cohort study evaluating 1,264 patients requiring mechanical ventilation found that high fever (≥39.5°C) was associated with increased risk for mortality in mechanically ventilated patients; however, in patients with sepsis, moderate fever (38.3°C-39.4°C) was protective, and antipyretic medication was not associated with changes in outcome [29]. Prospective data show that afebrile patients have higher 28-day mortality (37.5% vs 18.2%), increased acquisition of secondary infections (35.4% vs. 15.9%), and suppressed HLA-DR expression suggestive of monocyte dysfunction over time [30]. As recently as the 1910’s, the “malaria fever cure” (inducing fever to treat a range of conditions, an approach known as “pyrotherapy”) was widespread, with the originator of the idea receiving the Nobel Prize in Medicine or Physiology in 1927 [31,32]. Currently, the UK National Institute for Health and Care Excellence (NICE) recommend not using antipyretic agents “with the sole aim of reducing body temperature in children with fever [16,33]”. Actively inducing hyperthermia by directly heating the body has been used in cancer treatment, with minimal adverse effects [34-37]. Hyperthermia has been found to have positive impacts on the immune system, causing increased levels of heat-shock proteins [28,38,39], which are directly related to antigen presentation and cross‐presentation, activation of macrophages and lymphocytes, and activation and maturation of dendritic cells [40]. A pilot study of external warming of septic patients (ClinicalTrials.gov Identifier: NCT02706275) has recently been completed.

Many viruses replicate more robustly at cooler temperatures, such as those found in the nasal cavity (33–35°C) than at warmer core body temperature (37°C) [41-45]. Coronavirus disease 2019 (COVID-19) currently has limited treatment options besides dexamethasone [46], but its causative virus (SARS-CoV-2) may behave similarly to other viruses susceptible to temperature changes [47]. Simulations of the receptor binding domain (RBD) of SARS-CoV-2 found high flexibility near the binding site, suggesting that the RBD will have a high entropy penalty upon binding angiotensin-converting enzyme II (ACE2), and that consequently, the virus may be more temperature-sensitive in terms of human infection than other coronaviruses [48]. Notably, fever has often abated by the time a COVID-19 patient requires mechanical ventilation [49]. Additionally, patients with severe COVID-19 tend to have a high viral load and a long virus-shedding period, suggesting that the viral load of SARS-CoV-2 might be a useful marker for assessing disease severity and prognosis [50]. The aim of this study is to determine the effect of active core warming patients diagnosed with COVID-19 and undergoing mechanical ventilation. We hypothesize that active core warming will reduce the severity of acute respiratory distress syndrome, reduce the duration of mechanical ventilation, and improve survival compared to standard of care.

Study objectives

The purpose of the proposed pilot study is to determine if core warming improves respiratory physiology of mechanically ventilated patients with COVID-19, allowing earlier weaning from ventilation, and greater overall survival.

Determine the change in viral load measured in lower respiratory tract sample after implementation of core warming of ventilated patients, and compare this change to patients undergoing standard care.

Measure the impact of esophageal core warming on severity of acute respiratory distress syndrome as measured by PaO2/FiO2 ratio 24, 48, and 72 hours after initiation, and compare this to standard care.

Compare the duration of mechanical ventilation of patients treated with core warming to patients treated with standard care.

Compare the length of ICU and hospital stay of patients treated with core warming to patients treated with standard care.

Compare the 30-day mortality of patients treated with core warming to patients treated with standard care.

Methods

This is a single-center pilot study to evaluate if core warming improves respiratory physiology of mechanically ventilated patients with COVID-19, allowing earlier weaning from ventilation, and greater overall survival. The protocol was reviewed and approved by the Institutional Review Board of Washington University. The study is listed on ClinicalTrials.gov with identifier NCT04426344. This prospective, randomized study will include 20 patients diagnosed with COVID-19, and undergoing mechanical ventilation for the treatment of respiratory failure. Patients will be randomized in a 1:1 fashion with 10 patients (Group A) randomized to undergo core warming with an esophageal heat transfer device, and the other 10 patients (Group B) serving as the control group. Patients randomized to Group A will have the esophageal heat transfer device placed in the ICU or other clinical environment in which they are being treated after enrollment and provision of informed consent from appropriate surrogate or legally authorized representative. This study is posted on ClinicalTrials.gov with registration number: NCT04426344. The IRB of Washington University, St. Louis, is performing full review of the final protocol and expected to provide approval; the study will not start prior to IRB approval.

Screening

Subjects will be recruited from the ICU or other clinical environment in which they are being treated (Emergency Department, step-down unit, etc.). Patients will be identified by the PI or other study investigators/coordinators as available, and will be restricted to those who have been undergoing mechanical ventilation for three days or less. All patients without a DNR order with a diagnosis of COVID-19 and meeting inclusion criteria will be eligible for screening for any exclusion criteria. Written informed consent for the research study will be obtained from patient’s surrogate or legally authorized representative prior to enrollment. A formal screening log will be maintained for the trial, and available data on patients not entered into the study will be compared to those entered into the study. Baseline variables of patients entered into the study will additionally be compared by randomization arm.

Study intervention and monitoring

Participants who have a signed research study consent form (via surrogate or legally authorized representative) will be randomized in a 1:1 fashion to core warming or to standard of care (standard temperature management and treatment). The esophageal heat transfer device will be used according to FDA 510(k) labeling (for patient warming). Patient temperature measurements will be collected for both the device and standard-of-care arms during the study period (up to 72 hours). Device placement will be performed using standard protocol per instructions for use. The esophageal heat transfer device will be set to 42°C temperature after initial placement, and maintained at 42°C for the duration of treatment. All patients will have usual standard of care labs, vital signs, and imaging for patients in critical condition undergoing mechanical ventilation in the ICU. Specific parameters to be measured include PaO2 at regular intervals appropriate for patients undergoing mechanical ventilation, and FiO2 at the time of obtaining blood gases for PaO2 measurement, to allow calculation of P/F ratio.

Control group patients will be managed as per standard of care currently utilized in the ICU, which will include the use of other methods of temperature management as warranted. This would include warming with a forced air blanket only in hypothermic patients (core temperature < 36°C) or antipyretic therapy for febrile patients, as requested by the treating physician. Episodes of hypothermia are infrequent and transient in this population, and the current standard of care generally utilizes a permissive approach to fever (allowing patients to remain mildly febrile) which will continue in the control group without modification (no intentional elevation of temperature will be provided in the control group).

Study endpoints

The purpose of this pilot study is to determine initial estimates on outcomes (viral load, PaO2/FiO2 ratio, duration of mechanical ventilation, and mortality) in order to determine adequate sample size to properly power definitive studies. Measurements will be compared at time points 24, 48, and 72 hours after initiation. Sampling for viral measurements will utilize lower respiratory tract samples, as these have been shown to be of greater sensitivity and reliability for patient monitoring [47,51,52].

Primary study endpoints

The primary endpoint of this study will be:

Viral load measured in lower respiratory tract sample 72 hours after initiation of core warming

Secondary study endpoints include:

PaO2/FiO2 ratio 24, 48, and 72 hours after initiation of core warming

Duration of mechanical ventilation

Duration of ICU and hospital stay

Patient mortality

Patients above the age of 18 years old.

Patients with a diagnosis of COVID-19 on mechanical ventilation.

Patient maximum baseline temperature (within previous 12 hours) < 38.3°C.

Patients must have a surrogate or legally authorized representative able to understand and critically review the informed consent form.

Patients with contraindication to core warming using an esophageal core warming device.

Patients known to be pregnant.

Patients with <40 kg of body mass.

Patients with DNR status.

Patients with acute stroke, post-cardiac arrest, or multiple sclerosis.

Subject recruitment

Subjects will be recruited from the ICU or other clinical environment in which they are being treated (Emergency Department, step-down unit, etc.). Patients will be identified by the PI or other study investigators/coordinators as available. All patients without a DNR order with a diagnosis of COVID-19 and meeting inclusion criteria will be eligible for screening for any exclusion criteria. Written informed consent for the research study will be obtained from patient’s surrogate or legally authorized representative prior to enrollment. If a patient enrolled in the study gains the capacity to consent for him/herself while the study is in progress, the patient will be approached by a study team member and the consent document will be presented directly to the patient. All questions the patient might have will be answered. The patient will be given the opportunity to either withdraw from the study or sign the consent form. The patient will be informed that his or her decision to withdraw from the study will not affect his or her medical care

Duration of study participation

Participants will be involved for approximately 1 month, including screening, treatment, and follow-up. After consent, patient participation in the intervention phase will last 72 hours for active treatment. The follow up for determination of outcome and duration of mechanical ventilation will occur at 1-month post-treatment. Additional data will be collected via chart review.

Total number of subjects and sites

This single-site study aims to recruit and randomize 20 patients. It is expected that up to 30 subjects may be consented in order to produce 20 randomized & evaluable subjects.

Core temperature modulation

Core temperature control and warming will be performed with a commercially available esophageal heat exchange device (ensoETM, Attune Medical, Chicago, IL). This device is currently used world-wide for various patient temperature management goals, including post-cardiac arrest therapeutic hypothermia [Resuscitation. 2017 ">53-56], warming of burn patients [57], warming general surgical patients [58], cooling traumatic brain injury [59], cooling heat stroke [60], and the treatment of central fever [61,62]. The device is a multi-chambered silicone tube placed in the esophagus and connected to a heat exchanger to provide heat transfer to or from a patient (video available at https://vimeo.com/306506411). Modulation and control of the patient’s temperature is achieved by adjusting setpoint on the external heat exchanger, which in turn controls the circulating water temperature. Two lumens of the device connect to the external heat exchanger, while a third central lumen provides stomach access for gastric decompression or tube feeding. It is a single-use, disposable, non-implantable device with an intended duration of use of 72 hours or less.

Intervention regimen

Patients who are randomized to core warming will have the esophageal heat transfer device placed in the ICU or other treatment area where patient is undergoing mechanical ventilation. The device will remain in place until the study is completed (72 hours). The device will be set to 42°C for the duration of the study period. It is expected that patient temperature will increase from baseline by 1°C to 2°C, but due to ongoing heat loss from the patient, the expected maximum patient temperature is below 39°C. The time course of illness of COVID-19 is such that patients often no longer have fever by the time of mechanical ventilation [41]. If patient temperature increases above this range and reaches 40°C, the device will be set to an operating temperature of 40°C, thereby preventing any further increase in patient temperature. Patient temperature will be followed at intervals per standard of care in the intensive-care setting for mechanically ventilated patients (typically hourly).

Blinding

Due to the nature of this study, the physicians will not be blinded to the randomization assignment, however participants will be blinded. Once a subject is randomized, the research team will receive the randomization assignment (core warming or standard of care) and proceed with the procedures per the assignment.

Demographics (including sex/gender, race, ethnicity, and age via date of birth)

Past medical history, social history, physical exam findings and physicians notes

Concurrent medications

Physical exam

Vital signs: temperature, blood pressure, heart rate, respiration rate, height and weight

Clinical labs: complete blood count (CBC), chemistry profiles, liver function tests, inflammatory markers (CRP, ferritin), d-dimer, arterial blood gas for determination of PaO2

Upper (nasopharyngeal) and lower (tracheal aspirate, sputum) respiratory tract viral load (cycle threshold)

Severity of illness: APACHE III, sequential organ failure assessment (SOFA) scoring systems

Ventilator settings

Pregnancy test for women of childbearing age

Adverse events or unanticipated problems

Data collection

Data will be collected via chart review, and is expected to be available from routinely obtained laboratory and vital sign data recorded at routine intervals (i.e., when labs are drawn for routine care in the ICU).

Sample size and power determination

Based on a prior study in patients with sepsis, a maximum temperature of 38.3°C to 39.4°C was associated with survival (aHR 0.61 [95% CI, 0.39–0.99]) [29]. However, the effect of warming specific to COVID-19 patients remains uncertain, and as such, it is not possible to accurately perform a power calculation for this pilot study. It is believed that a total of 10 patients for each group will yield the sufficient pilot data to make an appropriate conclusion regarding the potential utility of core warming in reducing viral load, improving pulmonary physiology, reducing mechanical ventilation duration, and increasing patient survival. It is anticipated that data from this pilot study can be used for planning future larger studies.

Statistical methods

We will utilize standard measures to report outcomes and measure differences between groups. Specifically, we will use descriptive statistics, including mean (standard deviation) and median (interquartile range). Kaplan-Meier plots of important time to event outcomes and measures will be produced. Normality will be assessed using histograms and the Kolmogorov–Smirnov test. Formal hypothesis testing is not planned for this pilot feasibility study.

Efficacy analysis

This is a pilot feasibility study to determine the potential role of core warming during COVID-19 treatment.

Interim safety analysis

All subjects entered into the study and randomized at the baseline timepoint will have detailed information collected on adverse events for the overall study safety analysis. An interim safety analysis will be performed after the first 10 subjects are enrolled in the trial. At this time the safety and tolerability of the study device will be assessed and if deemed safe and appropriate, enrollment will continue to 20 subjects.

Subject population for analysis

All patients enrolled, randomized to a study arm, and completed in the study will be included for analysis.

Conclusion

We describe, before the initiation of any data collection, our approach to obtaining and analyzing data from a pilot randomized-controlled trial of core warming patients undergoing mechanical ventilation due to COVID-19. We anticipate this framework will enhance the utility of the reported results and provide a solid basis from which to design and execute subsequent investigations.

Case report form—core warming COVID-19.

(DOCX)

Click here for additional data file.

Consent template.

(DOCX)

Click here for additional data file.

Safety and monitoring—protocol—core warming in COVID-19.

(DOCX)

Click here for additional data file.

SPIRIT-checklist-core warming COVID.

(DOC)

Click here for additional data file.

Transfer Alert

This paper was transferred from another journal. As a result, its full editorial history (including decision letters, peer reviews and author responses) may not be present.

19 Jun 2020

Submitted filename: PLoS response to editor.docx

Click here for additional data file.

9 Sep 2020

PONE-D-20-12959

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study

PLOS ONE

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Reviewers' comments:

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The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: No

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2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #1: Yes

Reviewer #2: No

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Reviewer #2: Yes

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Reviewer #1: This study looks to carry out a small pilot project of 20 severely ill and ventilated COVID-19 patients equally randomised into one of two arms a) raising body temperature to an elevated degree but below 40C b) treatment as usual. The study aims to generate data regarding important clincial parameters in order to design a definitive clinical trial at a later date. They have already registered the trial at https://clinicaltrials.gov/ct2/show/NCT04426344.

I think the analysis would be enhanced if the authors state that they will produce Kaplan-Meier plots of important time to event outcomes/measures eg death, time on ventilation etc. Further I would like to see mention of a sceening log for this trial and a sentence of how they will report on this in order to give a fuller picture of what they will do/have done. Furthermore given the need for this to be an unblinded study, being able to compare who did and did not get entered into the study and to which arm, if entered, would be useful. I'd also like to see the 1st Exclusion removed as this is simply a negation of the last Inlcusion criteria, furthermore it doesnt exist on the kindly provided CRF.

They may also wish to slightly amend their introduction about there being no treatment in light of the RECOVERY trial result https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 and https://www.nejm.org/doi/10.1056/NEJMoa2021436 (full disclosure my brother is a co-author on these reports)

Reviewer #2: The authors outline a protocol for a randomized controlled pilot study of core temperature warming in mechanically ventilated patients with COVID-19 and its effects on viral load in the endotracheal tube (primary outcome) and several additional clinical outcomes including disease severity, hospital and intensive care unit length of stay, duration of

mechanical ventilation, and 30-day mortality. Though the rationale for the study is plausible, and certainly should be explored further, the manuscript does not provide adequate information on several key areas outlined below. Please note, it is very difficult to make comments on the manuscript without page numbers or line numbers.

1. Why was the viral load in the endotracheal tube chosen as the primary outcome? There is data on nasal/NP viral kinetics, but very little in endotracheal samples, and there is a high probability that this measurement will not demonstrate an appreciable difference between groups.

2. There is no description of the sample size calculation relative to the outcomes. Given the small sample size proposed, a more realistic outcome would be feasibility.

3. Duration of the study seems way too short to assess the outcomes being investigated – especially hospitalization duration and mortality.

4. There is no consideration for the duration of mechanical ventilation at the time of enrollment – there will be a meaningful difference in ability to assess outcomes depending on time since illness onset and time since ventilation.

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Reviewer #1: Yes: Greg Fegan

Reviewer #2: No

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15 Sep 2020

Thank you for the opportunity to submit our revised manuscript, PONE-D-20-12959,

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study.

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming.

We believe we now meet your style requirements.

2. At this time, we ask that you please specifically state that the protocol was reviewed and approved by the Institutional Review Board of Washington University

We have added this to the manuscript under the Methods section.

3. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

We are happy to provide our data, however it obviously will not be available for quite some time, since the study still has to be performed and completed. We hope that this protocol paper can nevertheless be published prior to completion of the study and analysis of the data.

4. Thank you for stating the following financial disclosure:

"EK declares equity interest in Attune Medical."

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Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

This amended role of funder statement is now included.

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competing interests: EK declares equity interest in Attune Medical."

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Updated competing interests statement is now included.

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These have been added.

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: No

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: No

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: No

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: No

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: This study looks to carry out a small pilot project of 20 severely ill and ventilated COVID-19 patients equally randomised into one of two arms a) raising body temperature to an elevated degree but below 40C b) treatment as usual. The study aims to generate data regarding important clincial parameters in order to design a definitive clinical trial at a later date. They have already registered the trial at https://clinicaltrials.gov/ct2/show/NCT04426344.

I think the analysis would be enhanced if the authors state that they will produce Kaplan-Meier plots of important time to event outcomes/measures eg death, time on ventilation etc. Further I would like to see mention of a sceening log for this trial and a sentence of how they will report on this in order to give a fuller picture of what they will do/have done. Furthermore given the need for this to be an unblinded study, being able to compare who did and did not get entered into the study and to which arm, if entered, would be useful. I'd also like to see the 1st Exclusion removed as this is simply a negation of the last Inlcusion criteria, furthermore it doesnt exist on the kindly provided CRF.

They may also wish to slightly amend their introduction about there being no treatment in light of the RECOVERY trial result https://www.medrxiv.org/content/10.1101/2020.06.22.20137273v1 and https://www.nejm.org/doi/10.1056/NEJMoa2021436 (full disclosure my brother is a co-author on these reports)

Thank you for your review and resulting suggestions for improvement.

We have specified that Kaplan-Meier plots will be produced.

We have now included the use of a formal screening log, and our plans to report on screening results, as well as entry versus non-entry into the clinical study.

We have removed the first exclusion criteria as suggested.

We have now amended the abstract, and modified the introduction to include the mention of this treatment option.

Reviewer #2: The authors outline a protocol for a randomized controlled pilot study of core temperature warming in mechanically ventilated patients with COVID-19 and its effects on viral load in the endotracheal tube (primary outcome) and several additional clinical outcomes including disease severity, hospital and intensive care unit length of stay, duration of mechanical ventilation, and 30-day mortality. Though the rationale for the study is plausible, and certainly should be explored further, the manuscript does not provide adequate information on several key areas outlined below. Please note, it is very difficult to make comments on the manuscript without page numbers or line numbers.

Thank you for your review and suggestions for improvement. We have now included page numbers and line numbers.

1. Why was the viral load in the endotracheal tube chosen as the primary outcome? There is data on nasal/NP viral kinetics, but very little in endotracheal samples, and there is a high probability that this measurement will not demonstrate an appreciable difference between groups.

As further clarification, we do not plan samples from the endotracheal tube itself, but rather lower respiratory tract samples, which have been shown to be more reliable and sensitive than upper airway samples. We have provided further references on this topic in the manuscript.

2. There is no description of the sample size calculation relative to the outcomes. Given the small sample size proposed, a more realistic outcome would be feasibility.

We do not intend to power this pilot for superiority. We have further emphasized the feasibility aspect of this study.

3. Duration of the study seems way too short to assess the outcomes being investigated – especially hospitalization duration and mortality.

We have utilized standard intensive care measures, where ICU, hospital, and 28 or 30 day mortality is most common. Because most severity of illness scoring systems are based on either in-hospital or 30 day mortality, we believe that deviating from this standard may introduce further interpretability challenges.

4. There is no consideration for the duration of mechanical ventilation at the time of enrollment – there will be a meaningful difference in ability to assess outcomes depending on time since illness onset and time since ventilation.

Yes, we agree. We expect that randomizatioin may help balance differences in duration of mechanical ventilation at the time of enrollment; however, we have now specified that patients will be screened only if undergoing mechanical ventilation for three days or less.

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Greg Fegan

Reviewer #2: No

Submitted filename: Response to Reviewers - Core warming.docx

Click here for additional data file.

26 Oct 2020

PONE-D-20-12959R1

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study

PLOS ONE

Dear Dr. Kulstad,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

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We look forward to receiving your revised manuscript.

Kind regards,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (if provided):

Editor - Thank you for resubmitting your paper. As promised, I sent it back to the original referees who are now almost completely satisfied save a few minor issues. Please carefully consider the comments below and reply directly to each in a cover letter with appropriate marked and linked changes to the manuscript. I look forward to receiving the next version which I will handle personally for timeliness.

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Partly

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Partly

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: The authors have satisfactorily accommodated all my previous request. This is the 2nd time I have seen this paper and I am happy with the paper to go ahead.

Reviewer #2: Thank you for your response. You have addressed my comments but there remain a few points that require additional thought/consideration:

1. I am still concerned about the primary endpoint – will any lower respiratory tract specimen be used? There are data suggesting differences between BAL, endotracheal tube aspirates, and sputum. What is a patient is no longer intubated at 72 hours? Will their BAL/endotracheal aspirate be compared to a sputum sample at 72 hrs? Sample type appears to be a confounder for interpretation of the results. Additionally, in line 159 the endpoint is still listed as endotracheal aspirate.

2. There is no discussion of how administration of antiviral therapy may affect the virologic endpoint. The population of interest (mechanically ventilated adults) would not uniformly receive remdesivir given current guidelines, however, some may either before study enrollment or after. Stratification could be an option.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Greg Fegan

Reviewer #2: No

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26 Oct 2020

Thank you for the opportunity to submit our revised manuscript, PONE-D-20-12959,

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study.

Reviewer #2: Thank you for your response. You have addressed my comments but there remain a few points that require additional thought/consideration:

Thank you for your review and suggestions for improvement.

1. I am still concerned about the primary endpoint – will any lower respiratory tract specimen be used? There are data suggesting differences between BAL, endotracheal tube aspirates, and sputum. What is a patient is no longer intubated at 72 hours? Will their BAL/endotracheal aspirate be compared to a sputum sample at 72 hrs? Sample type appears to be a confounder for interpretation of the results. Additionally, in line 159 the endpoint is still listed as endotracheal aspirate.

We have not attempted to limit lower respiratory tract specimens, since some sites may prefer a BAL, others a mini BAL, etc. The key point will be that the same approach will be used in both arms, such that this will not be a confounder.

Because the typical duration of mechanical ventilation for this patient population is between 8 to 10 days, we do not expect a large number of patients to be extubated before 72 hours. Nevertheless, if there are unexpected quicker recoveries, we would expect this to balance out between the two groups, barring a miraculous effect from the experimental treatment.

We have corrected the terminology in line 159.

2. There is no discussion of how administration of antiviral therapy may affect the virologic endpoint. The population of interest (mechanically ventilated adults) would not uniformly receive remdesivir given current guidelines, however, some may either before study enrollment or after. Stratification could be an option.

Because the treatment of this patient population is undergoing constant change, with different approaches emerging, and previous treatments being found to have essentially no effect (for example, remdesivir), we have avoided making explicit requirements for treatment. We instead rely on the fact that over the duration of the study, the specific treatments provided (and the changes in treatments that occur as new data or treatments emerge), will occur essentially equivalently between the two randomized groups. If there is a substantial imbalance, additional stratification will then likely be necessary. We expect that this pilot will give valuable baseline information in this regard.

Submitted filename: Response to Reviewers - Second revisions.docx

Click here for additional data file.

18 Nov 2020

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation: protocol for a randomized controlled pilot study

PONE-D-20-12959R2

Dear Dr. Kulstad,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice for payment will follow shortly after the formal acceptance. To ensure an efficient process, please log into Editorial Manager at http://www.editorialmanager.com/pone/, click the 'Update My Information' link at the top of the page, and double check that your user information is up-to-date. If you have any billing related questions, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Steven Eric Wolf, MD

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. Does the manuscript provide a valid rationale for the proposed study, with clearly identified and justified research questions?

The research question outlined is expected to address a valid academic problem or topic and contribute to the base of knowledge in the field.

Reviewer #1: Yes

Reviewer #2: Yes

**********

2. Is the protocol technically sound and planned in a manner that will lead to a meaningful outcome and allow testing the stated hypotheses?

The manuscript should describe the methods in sufficient detail to prevent undisclosed flexibility in the experimental procedure or analysis pipeline, including sufficient outcome-neutral conditions (e.g. necessary controls, absence of floor or ceiling effects) to test the proposed hypotheses and a statistical power analysis where applicable. As there may be aspects of the methodology and analysis which can only be refined once the work is undertaken, authors should outline potential assumptions and explicitly describe what aspects of the proposed analyses, if any, are exploratory.

Reviewer #1: Yes

Reviewer #2: Yes

**********

3. Is the methodology feasible and described in sufficient detail to allow the work to be replicable?

Reviewer #1: Yes

Reviewer #2: Yes

**********

4. Have the authors described where all data underlying the findings will be made available when the study is complete?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception, at the time of publication. The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

Reviewer #2: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

Reviewer #2: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above and, if applicable, provide comments about issues authors must address before this protocol can be accepted for publication. You may also include additional comments for the author, including concerns about research or publication ethics.

You may also provide optional suggestions and comments to authors that they might find helpful in planning their study.

(Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: No further comments to add as I had said when I looked at the 1st revision. My understanding of this work is to simply check what warming of severely sick COVID-19 patients may do in a small feasibility/pilot study.

Reviewer #2: The authors have adequately addressed all of my comments and I have no further concerns for publication.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: Yes: Greg Fegan

Reviewer #2: No

20 Nov 2020

PONE-D-20-12959R2

Core warming of coronavirus disease 2019 (COVID-19) patients undergoing mechanical ventilation – a protocol for a randomized controlled pilot study

Dear Dr. Kulstad:

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now with our production department.

If your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information please contact onepress@plos.org.

If we can help with anything else, please email us at plosone@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Steven Eric Wolf

Academic Editor

PLOS ONE

Study Phase	Screening	Randomization/Intervention Phase			Follow- up
Study Days	Day -1 to 0	Day 0	Day 1–2	Day 7, 14	Day 30
Informed Consent	X
Review Inclusion/Exclusion Criteria	X
Demographics	X
Medical History/Interim History*	X		X		X
Physical Examination*	X		X		X
Vital Signs: Temperature, BP, HR, RR*	X		X		X
Height and Weight	X
Pregnancy Test	X
Clinical Laboratory Evaluation	X	X	X
Respiratory tract viral load				X
Ventilator settings	X	X	X
APACHE III and SOFA scores	X	X	X
Clinical Imaging	X	X	X
Prior/Concomitant Medications	X				X
Randomization		X
Temperature monitoring		X	X
PaO2, FiO2, parameter recording		X	X
Discharge			X
Adverse Event / Unanticipated Problems Assessment		X	X		X

* Interim medical history, physical exam, and vitals will be collected via chart review from routine clinical care.