Contemporary Clinical Trials 88 (2020) 105893

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Contemporary Clinical Trials

journal homepage: www.elsevier.com/locate/conclintrial

A Phase II randomized controlled trial for lung and diaphragm protective T

ventilation (Real-time Effort Driven VENTilator management)
⁎
Robinder G. Khemania,b, , Justin C Hotza, Margaret J. Kleina, Jeni Kwoka, Caron Parkc,
Christianne Lanec, Erin Smitha, Kristen Kohlera, Anil Suresha, Dinnel Bornsteina,
Marsha Elkunovichb,e, Patrick A. Rossa,b, Timothy Deakersa,b, Fernando Beltramoa,b,
Lara Nelsona,b, Shilpa Shaha,b, Anoopindar Bhallaa,b, Martha A.Q. Curleyd,
Christopher J.L. Newtha,b
a
Children's Hospital Los Angeles, Department of Anesthesiology and Critical Care, United States of America
b
University of Southern California, Keck School of Medicine, Department of Pediatrics, United States of America
c
University of Southern California, Keck School of Medicine, Department of Preventative Medicine, United States of America
d
Children's Hospital Philadelphia, University of Pennsylvania, United States of America
e
Children's Hospital of Los Angeles, Department of Emergency Medicine, United States of America

A R T I C LE I N FO A B S T R A C T

Keywords: Lung Protective Mechanical Ventilation (MV) of critically ill adults and children is lifesaving but it may decrease
Ventilator induced lung injury diaphragm contraction and promote Ventilator Induced Diaphragm Dysfunction (VIDD). An ideal MV strategy
Mechanical ventilator would balance lung and diaphragm protection. Building off a Phase I pilot study, we are conducting a Phase II
Ventilator weaning controlled clinical trial that seeks to understand the evolution of VIDD in critically ill children and test whether a
Work of breathing
novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can balance lung
Pediatrics
and diaphragm protective ventilation to reduce time on MV. REDvent systematically adjusts PEEP, FiO2, in-
spiratory pressure, tidal volume and rate, and uses real-time measures from esophageal manometry to target
normal levels of patient effort of breathing. This trial targets 276 children with pulmonary parenchymal disease.
Patients are randomized to REDvent vs. usual care for the acute phase of MV (intubation to first Spontaneous
Breathing Trial (SBT)). Patients in either group who fail their first SBT will be randomized to REDvent vs usual
care for weaning phase management (interval from first SBT to passing SBT). The primary clinical outcome is
length of weaning, with several mechanistic outcomes. Upon completion, this study will provide important
information on the pathogenesis and timing of VIDD during MV in children and whether this computerized
protocol targeting lung and diaphragm protection can lead to improvement in intermediate clinical outcomes.
This will form the basis for a larger, Phase III multi-center study, powered for key clinical outcomes such as 28-
day ventilator free days.
Clinical Trials Registration: NCT03266016

1. Introduction physiologic levels of patient effort and diaphragm contraction, which

contributes to Ventilator Induced Diaphragm Dysfunction (VIDD).
Mechanical Ventilation (MV) necessitates careful attention to pre- VIDD is associated with longer length of ventilation, higher rates of
vent complications. Over the past 30 years, lung-protective ventilation weaning and extubation failure, and higher post-Intensive Care Unit
has been a focus, particularly for adults and children with Acute (ICU) morbidity and mortality [1–7].
Respiratory Distress Syndrome (ARDS). This includes: Positive End Alternatively, when patients have very high degrees of effort and
Expiratory Pressure (PEEP) to prevent atelectrauma, limiting tidal vo- diaphragm contraction, lung injury can be exacerbated through a
lume and driving pressure to prevent over-distension, and use of per- variety of mechanisms collectively termed patient self-inflicted lung
missive hypercapnia. To achieve lung protection, patients are often injury. These mechanisms relate to large negative swings in pleural
sedated or undergo neuromuscular blockade. This results in sub- pressures resulting in atelectrauma, high total transpulmonary driving

⁎
Corresponding author at: 4650 Sunset Blvd MS 12, Los Angeles, CA 90027, United States of America.
E-mail address: [email protected] (R.G. Khemani).

https://doi.org/10.1016/j.cct.2019.105893
Received 6 August 2019; Received in revised form 5 November 2019; Accepted 14 November 2019
Available online 16 November 2019
1551-7144/ © 2019 Elsevier Inc. All rights reserved.
R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

pressure, mechanical stretch of the alveoli, patient-ventilator asyn- the patient has spontaneous efforts, then this protocol also implements
chrony, and regional maldistribution of ventilation [8]. Furthermore, a rule set using esophageal manometry that adjusts recommendations
supra-physiologic patient effort also appears to have negative effects on to promote physiologic levels of patient effort. The feasibility of this
diaphragm architecture and function [3,9]. Ideally, MV strategies REDvent protocol was tested in 32 MV children with Pediatric ARDS
should provide lung protective levels of PEEP, driving pressure, and (PARDS) as part of a Phase I intervention only pilot study. This study
tidal volume while still promoting physiologic levels of patient effort of identified that protocol recommendations had high rates of adherence
breathing. (> 75%). REDvent patients compared to historical controls had PEEP
However, implementing a MV strategy that is both lung and dia- managed more in line with the ARDSNet low PEEP/FiO2 grid, had
phragm protective is challenging. Computerized decision support (CDS) lower tidal volume, and lower delta pressure (peak inspiratory pres-
offers advantages in circumstances where complex decisions require sure-PEEP). Patients managed with the REDvent protocol had on
weighing potentially competing risks, depending on the physiologic average 3 fewer days on MV with no significant difference in survival or
state of the patient. We employ such an approach using a CDS tool that re-intubation compared to matched historical controls [40].
promotes lung protective ventilation protocols for PEEP, tidal volume,
and inspiratory pressure coupled with a target of maintaining patient 3. Study methods for the REDvent phase II randomized controlled
effort of breathing in a physiologic range (as measured by esophageal trial (RCT)
manometry) whenever spontaneous breathing is permitted. This inter-
vention is called Real-time Effort Driven ventilator management 3.1. Main study aims
(REDvent), and in initial phases is targeting children with acute re-
spiratory failure, although the principles and techniques will likely be This is a single-center Phase II RCT (138 children per arm) using
applicable to adults. REDvent (intervention) as compared with usual care (control) venti-
lator management including a standardized daily Spontaneous
2. Preliminary studies Breathing Trial (SBT) (Funding: NIH/NHLBI R01HL124666). The cen-
tral hypothesis is that REDvent will reduce VIDD, leading to shorter
During usual care ventilation, there are lost opportunities to pro- time on MV. The primary question is to determine if REDvent acute
mote lung protective ventilation [10,11] and reduce ventilator settings and/or weaning phase protocols can shorten the duration of weaning
[11,12]. Ventilator driving pressures are often higher than necessary from MV (primary outcome). We expect that patients randomized to
and respiratory alkalosis is common, preventing meaningful patient receive REDvent will experience a shorter duration of weaning com-
effort [13,14–17]. Furthermore, while practitioners frequently target pared to usual care. Secondary outcomes include 28-day ventilator free
spontaneous breathing during the weaning phase, the level of ventilator days and extubation failure.
assistance is often high, and patient breathing effort is 2–4 times below Additional research questions surround [1] how changes to direct
the normal physiologic range of extubated patients [3,18]. This sub- measures of respiratory muscle strength, load, effort, and architecture
physiologic patient effort likely potentiates diaphragm weakness. throughout the duration of MV are related to weaning outcomes, and if
Accurate quantification of the severity of diaphragm dysfunction is these factors differ between control and intervention groups as well as
understudied in pediatrics. While diaphragm ultrasound can provide [2] to determine if patient effort of breathing during both acute and
corroborative data about architectural changes, ultrasound does not weaning phases of MV is independently associated with the develop-
directly measure strength [3,19–22]. Direct measures of respiratory ment of VIDD. Enrollment began in late 2017 and is anticipated to
muscle strength using maximal inspiratory pressure during airway oc- continue through 2023.
clusion (PiMax), either of the airway or esophagus, are regarded as the Inclusion Criteria
most appropriate tests in adults [23,24]. When patients are intubated,
there is divergence in the literature as to whether maximal voluntary 1. Children > 1 month (at least 44 weeks corrected gestational age)
efforts can be guaranteed [2,23,25–28]. Alternatively, some in- and ≤ 18 years of age AND
vestigators advocate twitch stimulation of the phrenic nerve, measuring 2. Supported on MV for pulmonary parenchymal disease (radiographic
change in airway pressure in response to a standardized brief stimula- evidence of alveolar or interstitial opacifications with a clinical risk
tion. This provides a measure of diaphragm strength, although the sti- factor for lung disease e.g. pneumonia, ARDS, aspiration, etc.) with
mulation is not sufficient for maximal activation and therefore is not Oxygen Saturation Index (OSI = (FiO2 * Mean Airway
directly measuring PiMax [23,29]. Although twitch stimulation has Pressure*100)/SpO2) ≥ 5 or Oxygenation Index (OI = FiO2 * Mean
been applied in a limited capacity in young children, it has high Airway Pressure*100)/PaO2)) ≥4 [41] AND
variability and limited reproducibility [30–35]. The measurement of 3. Within 48 h of initiation of invasive MV (72 h if transferred from
PiMax can provide insight into respiratory muscle function. In an another institution)
analysis of 409 patients at the time of extubation, we found that low
PiMax (both airway (aPiMax) and esophageal (ePiMax)) measured Exclusion Criteria
during airway occlusion while the child is breathing spontaneously, was
associated with re-intubation [36]. A trained provider performed 1. Contraindications to an esophageal catheter (i.e. severe mucosal
airway occlusion maneuvers, ensuring that the child was at end-ex- bleeding, nasal encephalocele, trans-sphenoidal surgery) OR
halation and that the airway remained occluded for 3–5 consecutive 2. Contraindications to use of Respiratory Inductance
breaths [28]. There was a dose response relationship between lower Plethysmography (RIP) bands (i.e. omphalocele, chest immobilizer
aPiMax and re-intubation risk, and children with aPiMax < 30 cm H20 or cast) OR
(35% of the population) had a nearly 3 fold higher risk of re-intubation 3. Conditions precluding diaphragm ultrasound measurement (i.e.
[37]. This suggests that respiratory muscle weakness is common in abdominal wall defects, pregnancy) OR
children and is associated with adverse outcome. 4. Conditions precluding conventional methods of weaning (i.e., status
The CDS tool used by REDvent is an electronic protocol that makes asthmaticus, severe lower airway obstruction, critical airway, in-
recommendations at user-set time intervals, using a pediatric mod- tracranial hypertension, Extra Corporeal Life Support (ECLS), lim-
ification of the Acute Respiratory Distress Syndrome Network itation of care, severe chronic respiratory failure, spinal cord injury
(ARDSNet) protocol for pressure control ventilation [38]. We have above lumbar region, cyanotic heart disease (unrepaired or pal-
demonstrated that pediatric critical care practitioners generally agree liated) OR
on the recommendations generated by the modified protocol [39]. If 5. Primary Attending physician refusal

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R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

for infants with bronchiolitis who are maintained on high flow nasal
cannula (> 75% have PRP over 400), and slightly lower than the ty-
pical PRP range for infants on nasal Continuous Positive Airway Pres-
sure (CPAP) [46,47]. Therefore, this range appears to result in effort of
breathing even lower than what most critical care clinicians would
deem acceptable for critically ill children who are not on MV. While it is
possible that respiratory muscle oxygen consumption could be in-
creased near the upper limit of this range, in our previous pilot study we
found that lower targets or a more narrow range (i.e. keeping PRP close
200) resulted in very frequent titrations of ventilator support which was
difficult to implement in clinical practice. Furthermore, normal varia-
tion in breathing pattern and in response to stimulation in infants and
young children often results in PRP changes of 100–200, making it
important to maintain a slightly larger range for practicality and clin-
ical acceptability.
The esophageal balloon is inflated to a prescribed volume every 4 h
prior to assessment, based on an optimal filling volume algorithm. The
median PRP over 10–20 breaths during calm periods of breathing (i.e.
not agitated, not recently suctioned) is entered into the CDS tool. High
Frequency Oscillatory (HFO) Ventilation can be used as a rescue
therapy as per the decision of the bedside clinicians, but HFO man-
agement is protocolized using the HFOV CDS tool (expected use:
10–15% in this cohort). This HFO protocol has a MAP/FiO2 table, and
also recommends alterations in Power (Amplitude) and Frequency
(Hertz) based on pH.
Control Arm: Ventilator management will be per usual care until the
patient meets weaning criteria and passes the oxygenation test (Fig. 2).
Regardless of treatment group, patients will have an esophageal
manometry catheter placed. Daily measures of patient effort (PRP),
transpulmonary pressures, and diaphragm thickness and contractile
activity will occur. Once the patient passes the oxygenation test, an
Fig. 1. High level overview of study protocol in both acute and weaning phases. airway occlusion maneuver will be performed to measure neuromus-
cular strength (PiMax), using previously validated techniques which
This study seeks to understand whether it is important to implement consist of continuous airway occlusion at end-exhalation for 3–5 breath
these lung and diaphragm protective protocols near initiation of MV attempts [37,48,49]. Patients will subsequently undergo an SBT, during
(acute phase) or if there is also benefit during the weaning phase of which RIP bands will be placed to monitor thoraco-abdominal asyn-
ventilation. As such, acute phase randomization occurs upon study chrony. The primary study outcome (length of the weaning phase) is
enrollment, and patients who fail the first SBT undergo a weaning phase defined as the time from initiation of the first SBT until successful
randomization (Fig. 1). passing of an SBT (or extubation, whichever comes first). Patients who
fail the initial SBT will move on to the weaning phase, and will undergo
the weaning phase randomization to allocate treatment or control arms
3.2. Acute phase for weaning management.

The acute phase is defined as the time from intubation until the 3.3. Spontaneous breathing trials (SBTs)
patient meets weaning criteria [42,43], and passes the initial oxyge-
nation test (decrease PEEP to 5 cmH2O and FiO2 to 0.5, Fig. 2). All SBTs are performed on CPAP of 5 cm H2O (without PS), with
patients are screened daily to determine if they meet weaning criteria, FiO2 ≤ 0.5. If any failure criteria are met during the 2-hour SBT
and if they are eligible for the oxygenation test. (Table 1), the patient will be labeled as failing the SBT for study pur-
Intervention Arm (REDvent-acute): Patients will be managed in a poses. At this point, the clinical team may choose to stop the SBT, and
synchronized intermittent mandatory ventilation mode with pressure the patient is returned to the previous ventilator settings, and weaning
control plus Pressure Support (PS) with a CDS tool recommending phase randomization will occur. The clinical team may alternatively
changes to ventilator settings every 4 h or with a new blood gas. Details choose to continue the SBT or to extubate the patient. If the patient is
of the rules behind the actual protocols are in the appendix. PEEP/FiO2 not extubated within 6 h of SBT failure, then weaning phase rando-
management is based on the low PEEP/FiO2 table from the ARDSNet mization will occur.
protocol [38]. Ventilation is changed based on pH range, peak in- If the patient successfully passes the SBT, the primary outcome is
spiratory pressure, and ventilator rate. When the patient is breathing achieved. However, the decision to extubate is left to the clinical team.
spontaneously during the acute phase, the Pressure Rate Product (PRP If the patient is not extubated within 6 h of passing the SBT, acute phase
= peak to trough change in esophageal pressure*respiratory rate) from management (to whichever group they were randomized) is resumed
esophageal manometry is incorporated into the algorithm, targeting until extubation. A SBT is repeated daily until extubation. The reasons
maintaining PRP in a physiologic range of 200–400. for not extubating after passage of an SBT are collected (i.e. inadequate
This PRP range was established based on the typical range cough, gag, handling secretions, feedings not interrupted, procedures
(25–75%) for patient effort of breathing 60 min after successful ex- planned).
tubation, using data from approximately 400 mechanically ventilated
critically ill children [44,45]. This range of PRP corresponds to a 3.4. Weaning phase
pressure-time product range between 75 and 200. In addition, we have
also found this range is significantly lower than the typical PRP range The weaning phase is defined as the time from the first SBT until the

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R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

Fig. 2. Acute vs. weaning phase interventions and monitoring for both intervention and control patients.

Table 1
Spontaneous breathing trial passage criteria.
Variable Failure within 2 h

pH (arterial or capillary) < 7.32

End tidal CO2 ↑10 mmHg from baseline
Oxygenation FiO2 > 0.5 and SpO2 < 90% on
PEEP = 5 cmH20
Heart rate ↑ > 40 BPM over baseline
Rapid Shallow Breathing Pattern ≥12
(RSBI) (bpm/ml/kg)
Pressure Rate Product (PRP) > 500
Retractions Moderate or Severe Retractions

patient successfully passes an SBT. SBTs are performed daily during the
weaning phase, along with measurement of PiMax with airway occlu-
sion maneuvers.
Intervention Arm (REDvent-weaning): Patients will be managed in a
PS/CPAP mode of ventilation and PRP will be monitored continuously,
adjusting PS (to a max of 20 cmH20) every 4 h to maintain PRP in the
target range (Fig. 3). PEEP may be adjusted between 5 and 10 cmH20.
Weaning phase intervention continues until extubation.
Control Arm: Ventilator management will be per usual care as de-
termined by the treating clinical team until the patient is extubated.
The decision to use non-invasive ventilation and other post-ex-
tubation management will not be protocolized, regardless of study arm.
Suspension of the study intervention is permitted for up to 12 h for
invasive procedures, or rapid changes in patient status. If the inter-
vention is suspended for > 12 h, it is considered a protocol violation
and continued participation in the study will be discussed with the
primary attending physician. For patients in the weaning phase who
have suspension of the protocol and no longer meet weaning criteria at
the 12-hour mark (Fig. 2), the acute phase management is resumed. The
Fig. 3. Weaning phase interventions.
patient will be managed as per their pre-assigned acute phase group.
Once weaning criteria are met, an SBT will again be performed. If the

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R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

Table 2
Data collection timeline.

patient fails the SBT, then the weaning phase intervention to which 3.6. Co-interventions
they were previously randomized is resumed. If the patient has not
passed the SBT by day 28 after enrollment, study interventions and Sedation management is the same in both arms and includes tar-
daily measurements will be terminated. All ventilator management will geted sedation guided by the State Behavioral Scale (SBS) [50]. Inhaled
be as per usual care. Clinical outcomes will continue to be followed. nitric oxide is permitted as per the discretion of the clinical team. For
Patients who develop exclusion criteria after study enrollment that patients in the intervention group, weaning of nitric oxide will be re-
preclude continuation of the study interventions (i.e. use of ECLS, new commended once FiO2 is reduced below 0.6, which is in line with the
condition requiring removal of esophageal catheter) will have the study standard clinical practice in the PICU.
protocol and measurements terminated, but clinical outcomes will
continue to be followed and analysis will be as per Intention-To-Treat
(ITT). 4. Statistical considerations

4.1. Randomization strategy and blinding

3.5. Data collection
For the acute phase, subjects will be block randomized to either arm
Demographics, clinical variables, and outcomes will be measured as stratified by age group: infant (30 days −365 days), child (366 days to
detailed in Table 2. To ensure the adequacy of randomization and un- ≤8 years), and older child/ adolescent (9–18 years); and immune
derstand the risk factors that may contribute to neuromuscular weak- suppression (congenital or acquired conditions that result in marked
ness and weaning failure, we will gather detailed, serial data for vari- inability to respond to antigenic stimuli). Block randomization will be
ables that may be related [1–7]. Identical measurements of respiratory based on random block sizes of 4, 6 and 8 within the strata above, and
parameters will occur for all patients enrolled in the study (regardless of are loaded into a central database for implementation. Weaning phase
study arm) [1] serially during both acute and weaning phases, [2] randomization is block randomized by acute phase group, and age
during airway occlusion prior to SBTs, and [3] during SBTs. using the same methodology. Although blinding is not possible given
the open label nature of the intervention, analysis will be blinded to
treatment groups.

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R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

4.2. Analysis plan compare difference between groups. Logistic regression will be used to
assess dichotomous outcomes, and a multinomial/ordinal logistic re-
Baseline characteristics at the time of randomization will be com- gression will be used for categorical outcomes (> 2 categories) while
puted for each treatment group (REDvent and usual care) and within adjusting for covariates. To assess the association between 2 continuous
each phase (Acute and Weaning). For all analyses, assumptions for data variables, a Pearson or Spearman correlation will be used, and analysis
distribution will be assessed, and transformations of the data or non- of covariance (ANCOVA) will be used to adjust for covariates. Gen-
parametric analysis will be performed as necessary. The mean and eralized Estimating Equation (GEE) will be used when necessary to
standard deviation will be reported for normally distributed continuous control for repeated measures. Sensitivity, specificity, and overall dis-
variables, and the median and interquartile ranges will be reported for crimination of predictive models will also be reported. Analyses will be
non-normally distributed continuous variables. Given this is an RCT, we performed using the appropriate recent version of the SAS statistical
anticipate balanced baseline characteristics. To evaluate this, we will software (SAS Institute Inc., Cary, NC). Power analysis and more de-
calculate effect sizes for measures of central tendency (Cohen d, Cramer tailed analytic plans are provided in the appendix.
v) between and across groups. For non-parametric variables, effect sizes
defined for the Mann-Whitney U will be calculated to produce r. For 5. Human subjects and data monitoring
frequency counts and percentages the rate ratio will be evaluated to
calculate the effect size. Variables that have more than a small effect The subjects of this study are intubated infants and children who
size (d > 0.2, v > 0.01, or r > 0.1, categorical effect size > 1.2) will not be able to consent for their own participation in this study.
indicate potential imbalances in baseline characteristics between Parents will be informed about the study and given an opportunity to
groups. These variables will be included in sensitivity analyses after the voluntarily give their permission for their child to participate. Assent of
primary ITT analyses are performed. subjects of appropriate age and capacity will be obtained after sedation
Retention, adherence, and missing data will be compared between has cleared to ensure permission for continued data collection until
and across groups. High levels of missing data are not anticipated given hospital discharge. The protocol has been approved by the Children's
the nature of the study. If the missing data is determined to be related to Hospital Los Angeles (CHLA) Institutional Review Board, as well as an
the outcome (not missing at random) or related to group or a covariate independent Data Safety and Monitoring Board.
(missing at random), we will explore the impact of these biases in All outcomes are independently extracted and verified by at least
sensitivity analyses after the primary ITT analyses using multiple im- two members of the research team. A vast majority of the data are
putation processes. Our primary approach to imputing missing data is collected through automated electronic feeds. A trained study data
the Markov Chain Monte Carlo (MCMC) simulation. Statistical Analysis collector uses extracts from the electronic feeds in conjunction with
Software (SAS) procedures will be used. data in the electronic health care record to populate study specific Case
The primary analysis seeks to address if there are differences in Report Forms (CRFs). Data collection occurs in real-time. Respiratory
length of weaning between: 1) REDvent-acute compared to usual care- measurements are entered into web-based CRFs at the time of study
acute, 2) REDvent-weaning compared to usual care-weaning, and 3) measurements (Research Electronic Data Capture (REDCap)). In addi-
REDvent-acute and weaning (combined) compared to usual care acute tion, raw data from esophageal manometry and RIP are recorded during
and weaning (combined). Analyses of these aims will follow the ITT each measurement, and the calculations are post-processed to verify the
principle. The primary analyses will compare median weaning duration real-time data entry. Ultrasound images are interpreted in real-time and
between groups using a Mann-Whitney U test, or a t-test with trans- calculations entered into the web-based CRF. In addition, all ultrasound
formation as necessary. The effect size (r) will also be computed to images are uploaded to a secure server, and undergo blinded inter-
assess the magnitude of treatment effect. If imbalances in baseline pretation by a single provider. Data validity and quality checks are
characteristics are found between or across randomized treatment performed weekly. All application software is hosted securely on the
groups, a Cox proportional hazard ratio will be performed to adjust for CHLA/University of Southern California network, which is protected by
covariates. The estimates (mean, median, or hazard ratio) and the as- several firewalls and security is monitored and audited regularly.
sociated 95% confidence interval, as well as the p-values, will be pre-
sented for interpretation. 6. Conclusions
Power analysis: For the primary outcome (weaning duration), a 1-
day change in length of weaning is considered clinically significant. It is Completion of this Phase II clinical trial will provide important in-
anticipated that up to 13% of patients may not achieve the primary formation on whether this computerized protocol targeting lung and
outcome (successful passage of an SBT or extubation due to death or diaphragm protection can lead to improvement in physiologic out-
dropout), and these patients will not be included in the primary out- comes and intermediate clinical outcomes. This will form the basis for a
come analysis, but will be included in secondary outcomes. We are larger, Phase III multi-center study.
targeting an overall sample size of 276 patients, with a minimum of 240
patients (120 per arm) available for analysis of the primary outcome. Acknowledgements
Using the two planned statistical tests above, this sample size would be
able to detect a ≥ 1-day change in weaning duration with a two-sided All authors made substantial contributions to the design or con-
alpha of 0.05 and power of 0.9, or a relative hazard ratio of 1.5 (ratio ception of the work, drafted and or revised the manuscript for im-
between control/intervention group) with a power of 0.9 or a hazard portant intellectual content, gave final approval of the version to be
ratio of 1.4 with a power of 0.8. Patients who fail the initial SBT will published and are accountable for all aspects of the work.
undergo the weaning phase randomization. From our pilot data, ap-
proximately 25% of patients exposed to the intervention passed the Funding sources
initial SBT, corroborating previous studies [42]. Anticipating 180 pa-
tients (90 per arm) will receive weaning phase interventions, there will United States of America National Insititutes of Health (NIH)/
be adequate power to detect a ≥ 1 day change in the length of the National Heart Lung and Blood Institute (NHLBI) R01HL124666.
weaning phase, or a hazard ratio of 1.5 with an alpha of 0.05 and power
of 0.8. Appendix A. Supplementary data
The analytic approach for secondary aims and outcomes such as
mortality and ventilator free days (Table 2) will follow those described Supplementary data to this article can be found online at https://
above. For categorical data, a χ2 or Fisher's exact test will be used to doi.org/10.1016/j.cct.2019.105893.

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R.G. Khemani, et al. Contemporary Clinical Trials 88 (2020) 105893

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