Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT03266016 |
| Other study ID # |
CHLA-17-00235 |
| Secondary ID |
5R01HL134666 |
| Status |
Active, not recruiting |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
October 21, 2017 |
| Est. completion date |
May 15, 2025 |
Study information
| Verified date |
April 2024 |
| Source |
Children's Hospital Los Angeles |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
This study is a Phase II controlled clinical trial that will obtain comprehensive, serial
assessments of respiratory muscle strength and architecture to understand the evolution of
ventilator-induced respiratory muscle weakness in critically ill children, and test whether a
novel computer-based approach (Real-time Effort Driven ventilator management (REDvent)) can
preserve respiratory muscle strength and reduce time on MV. REDvent offers systematic
recommendations to reduce controlled ventilation during the acute phase of MV, and uses
real-time measures from esophageal manometry to adjust supported ventilator pressures such
that patient effort of breathing remains in a normal range during the ventilator weaning
phase. This phase II clinical trial is expected to enroll 276 children with pulmonary
parenchymal disease, anticipated to be ventilated > 48 hrs. Patients will be randomized to
REDvent-acute vs. usual care for the acute phase of MV (interval from intubation to first
spontaneous breathing trial (SBT)). Patients in either group who fail their first Spontaneous
Breathing Trial (SBT), will also be randomized to REDvent-weaning vs. usual care for the
weaning phase of MV (interval from first SBT to passing SBT). The primary clinical outcome is
length of weaning (time from first SBT until successful passage of an SBT or extubation
(whichever comes first)). Mechanistic outcomes surround multi-modal serial measures of
respiratory muscle capacity (PiMax), load (resistance, compliance), effort (esophageal
manometry), and architecture (ultrasound) throughout the course of MV. Upon completion, this
study will provide important information on the pathogenesis and timing of respiratory muscle
weakness during MV in children and whether this weakness can be mitigated by promoting more
normal patient effort during MV via the use of REDvent. 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.
Description:
Study Aims:
SA1: To determine if REDvent acute and/or weaning phase protocols can shorten the duration of
weaning from MV (Primary outcome).
SA2: To determine if changes to direct measures of respiratory muscle strength, load, effort,
and architecture throughout the duration of MV are related to weaning outcomes.
SA3: To determine if patient effort of breathing during both acute and weaning phases of MV
is independently associated with the development of respiratory muscle weakness.
Study Design: Single-center randomized controlled trial (138 children per arm) using REDvent
(intervention arm) as compared with usual care ventilator management including a standardized
daily SBT (control arm). Acute phase randomization will occur upon study enrollment, and
patients who fail the first SBT will undergo a weaning phase randomization. The investigators
will obtain serial measurements of respiratory system capacity, load, effort of breathing,
and diaphragm architecture throughout the course of MV.
Acute Phase: The acute phase is defined as the time from intubation until the patient meets
weaning criteria, passes the initial oxygenation test (decrease PEEP to 5 cmH2O and FiO2 to
0.5, maintains SpO2 > 90%), and undergoes a Spontaneous Breathing Trial (SBT).
1. Intervention Arm (REDvent-acute): Patients will be managed with pressure control plus
pressure support ventilation using a computerized decision support tool that will
recommend changes to ventilator settings approximately every 4 hr (with or without a new
blood gas). If the patient is spontaneously breathing, it will incorporate real-time
measures of effort of breathing (esophageal manometry) to keep it in a target range.
2. Control Arm (Control-acute): Ventilator management will be per usual care until the
patient meets weaning criteria and passes the oxygenation test.
Weaning Phase: The weaning phase is defined as the time from the first Spontaneous Breathing
Trial (SBT) until the patient successfully passes an SBT or is extubated (whichever comes
first). Patients who pass the initial SBT at the end of the acute phase will not undergo
weaning phase randomization.
1. Intervention Arm (REDvent-weaning): Patients will be managed in a pressure support/CPAP
mode of ventilation with assessments or changes to the level of pressure support every 4
hours, targeting maintaining effort of breathing (esophageal manometry) in a normal
range. An SBT will be conducted daily, and the weaning phase will continue until the
patient passes the SBT.
2. Control Arm (Control-weaning): Ventilator management will be per usual care. An SBT will
be conducted daily, and the weaning phase will continue until the patient passes the
SBT.
Analysis Plan and Sample Size Justification:
Aim 1: The primary outcome is weaning duration. Sample size has been determined to adequately
power 3 separate comparative analyses: (a) REDvent-acute versus Acute Phase control (b)
REDvent-weaning phase versus Weaning Phase control (c) REDvent both phases versus control
both phases. Power is based on 2 planned methods for analysis: cox proportional hazard ratios
for multivariable analysis and univariate analysis with an independent t-test using log
transformation (as needed) to account for the expected distribution of weaning duration. For
all three of the planned comparisons above, with the proposed sample size the investigators
would be adequately powered (>0.8) to detect a difference in weaning duration of ≥ 1 day, or
a hazard ratio of ≥ 1.4 between groups. The secondary outcomes are ventilator free days and
extubation failure. Directly comparing control only patients to REDvent only patients, with
an expected standard deviation for VFDs between 5 to 9 days, the investigators will be able
to detect a 2-day change in VFDs between groups with a power between 0.35 and 0.82.
Re-intubation rates are expected to be 10%, allowing the investigators to confirm that
REDvent is not inferior to usual care in regards to re-intubation with a non-inferiority
margin of 0.10 with a power of 0.8 and alpha of 0.05.
Aim 2: The primary outcome of this aim is weaning duration. For respiratory muscle strength
the investigators will compare the first measured aPiMax (after resolution of the acute
phase, before the first SBT), the trajectory and value of the daily aPiMax during the weaning
phase prior to extubation, the lowest and highest measured aPiMax, and aPiMax on the day of
extubation against weaning duration. For analysis, aPiMax will be dichotomized at 30 cmH2O,
and weaning duration will be compared between patients with aPiMax > 30 versus ≤ 30 cmH2O
using a t-test with or without log-transformation, or Mann-Whitney U test, depending on the
distribution. From preliminary data, it is anticipated at least 35% of patients (n=84) will
have aPiMax ≤ 30 cmH2O. Based on a similar power analysis as presented above, this would
allow the investigators to determine whether low aPiMax is associated with a ≥ 1-day increase
in weaning duration, with an alpha of 0.05 and power of 0.8. The investigators will perform
identical analysis for ePiMax. Diaphragm Thickness analysis will compound daily ultrasound
measures to detect the relative change in diaphragm thickness from study day 1 until passage
of an SBT. The investigators will compare the change in thickness after resolution of the
acute phase (on the day of the first SBT) against weaning duration, in a similar manner as
proposed above for aPiMax. In addition to weaning duration, the investigators will also
examine whether the respiratory measures taken just prior to or during each SBT are
associated with the patient passing the SBT. For example with aPiMax and ePiMax, the
investigators will examine if there is a dose response relationship between PiMax measured
just before the SBT and the rate of passage of the subsequent SBT.
Aim 3: The primary outcome of this aim is aPiMax < 30 cmH2O.The analysis will focus on
determining whether the degree of patient effort of breathing is independently associated
with the development of respiratory muscle weakness. For the acute phase, the investigators
will generate a time-weighted average PRP during the acute phase and graph it against aPiMax
at the first SBT. They will subsequently dichotomize aPiMax at the first SBT and compare mean
time weighted average PRP in the acute phase between aPiMax groups (> 30 vs. ≤ 30 cmH2O). For
the weaning phase, the investigators will graph the changes in aPiMax throughout the weaning
phase (from first failed SBT until successful SBT) against time-weighted average PRP, with
the anticipation that low PRP will be associated with either further reductions in aPiMax, or
no improvement, while PRP in the physiologic range of 150-400 will be associated with
improvement in aPiMax. The investigators will subsequently dichotomize aPiMax (at 30 cm H2O)
at the time of successful passage of an SBT and compare time-weighted average PRP in the
weaning phase between aPiMax groups. Subsequently, the investigators will build a
multivariable logistic regression model on the outcome of aPiMax ≤ 30 cmH2O to determine if
time-weighted PRP in the acute phase, weaning phase or both have an independent association
with preserving aPiMax, after controlling for confounding variables.
