Clinical Trial Details
— Status: Active, not recruiting
Administrative data
| NCT number |
NCT04850079 |
| Other study ID # |
2018-2806 |
| Secondary ID |
|
| Status |
Active, not recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
September 28, 2018 |
| Est. completion date |
December 2024 |
Study information
| Verified date |
June 2024 |
| Source |
Children's Hospital Medical Center, Cincinnati |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
This observational study is designed to evaluate the integration of a model-informed,
clinically individualized pharmacokinetics (PK) profile (precision dosing dashboard) into
prescribing clinicians' existing workflows to improve safety and efficacy of morphine dosing
for neonates. The investigators will use user-centered participatory design methods and
real-time analysis to inform the refinement of the recently developed Electronic Health
Record (EHR) model-based decision support tool and test it during the pre-and
post-implementation stages.
Description:
Aim 1: To successfully implement a morphine PK and individualized precision dosing decision
aid into workflows of neonatal prescribing clinicians.
This study will evaluate the steps required to successfully implement a population
pharmacokinetic (PK) model-informed real-time decision support interface for the prescribing
of neonatal pain and sedation medications. Currently, most opiate and benzodiazepine
treatment is done by empirical dosing without any knowledge of drug concentrations, which can
easily lead to under or over-dosing of medications. Background data show that over 65% of
infants who are placed on morphine experience blood concentrations well above the currently
suggested target ranges. This project will incorporate PK model-informed dosing and
eventually include real-time drug concentration information feedback directly into
prescribers' workflows so that they can make a data-informed decision, thus allowing maximal
therapeutic efficacy while minimizing the likelihood of adverse events. The expected outcomes
are better clinical efficacy and safety with fewer side effects in the neonatal population.
Study design Open label, prospective, quasi-experimental study that will use data collected
during patients' Neonatal Intensive Care Unit (NICU) hospitalization at Cincinnati Children's
Medical Center (CCHMC).
The study will use user-centered participatory design methods to establish the optimal means
of incorporating this decision support into already existing workflows. These findings will
allow the investigators to implement the clinical decision support directly into clinical
practice during the study period. During and following implementation, the investigators will
use a mixed methods approach through continually evaluating the effectiveness of the
precision dosing application through technical analytics, real-time user feedback, and
clinical data feedback. Technical process outcomes will consist of usage analysis statistics
such as application access logs, time spent viewing the application, and technical error
rates (e.g., failure of the application to launch or load data). Users will have the option
to provide direct in-app feedback. Such feedback is necessary for successful agile software
development and will be incorporated into regular revisions of the tool. In addition, the
investigators will use clinical data including subjective bedside pain and sedation
assessments as well as objective morphine concentration data to help further refine the PK/PD
models.
Prospective evaluation of the decision support tool The investigators will start using the
tool to provide dosing guidance based on patient information and the morphine PK model
predictions but without using morphine concentrations as feedback for 3-6 months. This is
anticipated to be the time required to prospectively test the tool while putting in place the
logistics for timed sampling and morphine concentration measurements in real-time. Only
members of the study team will have access to the tool at this time. When the clinical team
is discussing the morphine usage over the last 24 hours and before the pain/sedation plan is
developed, the member of the study team that is reviewing the tool will introduce this
information on rounds. Currently the NICU clinical pharmacist on the study team reviews
NeoRelief during rounds to assess morphine doses being used and the estimated concentrations
based on the model. The tool will be made available to the other members of the study team as
part of the roll out. The model-based dosing suggestions are not meant to take the place of
clinical judgement. It is impossible to take into account all of the unique variables that go
in to developing a pain management plan for a patient. If the clinical team choses to deviate
from the recommendations, the clinical pharmacists will make a note as to why the decision
was made to deviate from the recommendation.
Once the logistics of morphine concentration measurement and reporting by the mass
spectrometry laboratory have been worked out, the investigators will continue with the
prospective evaluation of the decision support tool by now also taking into account morphine
concentration measurement(s) as 'feedback' using remnant samples. This will allow for
Bayesian estimation and prediction of a patient's individual PK profile. Again, since the
goal is the incorporation of the tool into the workflow, only members of the study team will
have access to the tool information. When the team is discussing the morphine usage over the
last 24 hours and before the pain/sedation plan is developed this information will be
introduced on rounds. This will provide the investigators with an objective way to determine
if it is being effectively incorporated into the workflow.
Study population and inclusion criteria:
Participants will be preterm and term neonates who receive intravenously (IV) administered
morphine for 24 hours or more in the CCHMC NICU as part of standard clinical pain care
management. The study target is a minimum of 200 evaluable research participants. All infants
in the CCHMC NICU regardless of gender, race, or age are potential subjects. The
investigators anticipate that enrolled participants will be of mixed demographics. There will
be no exclusions based on gender or ethnicity.
Data Collection and Management:
A central electronic database will be constructed for storing all study-related data. REDCap
will be used as the database software and will be password protected. REDCap is a secure,
web-based application for building and managing online surveys and databases and a resource
of the Center for Clinical and Translational Science and Training provided to researchers
affiliated with the University of Cincinnati Academic Health Center. Access will be
restricted to the primary investigator and designated study personnel.
Demographic and Clinical Data: Patient demographic data and clinical data will be collected
from the electronic medical record EPIC. Data to be collected will include:
- Patient ID
- Birth measurements - weight, length, head circumference
- Age - estimated gestational, chronological, corrected gestational, postmenstrual
- Diagnosis
- Post-operative complications, as applicable
- Date and time of morphine initiation
- Morphine dose and infusion rates
- Times and changes to morphine infusion rates
- Time and dose of any morphine boluses given
- Prior history of opiate and benzodiazepine exposure
- Concomitant medications and any other medication levels
- Medical conditions and diagnoses
- Laboratory values - Creatinine and transaminases
- Vital signs - heart rate, respiratory rate, blood pressure, and oxygen saturation
- NPASS scores: Along with physiologic indicators of pain (i.e., vital signs), behavioral
indicators of pain will be collected using the Neonatal Pain Agitation and Sedation
Scale. The NPASS is a validated pain scoring system that incorporates crying and
irritability, behavioral state, facial expression, extremity tone, and vital signs (HR,
RR, BP, SaO2) to assess neonatal pain and sedation that is consistently used in the
CCHMC NICU.
- Withdrawal Assessment Tool - Version 1 (WAT-1) scoring for signs of withdrawal (if
available); otherwise by collecting data on patients subjectively withdrawing, and/or
requiring a taper as per the clinical team.
The study will include the collection of discarded blood samples (remnant samples) from
neonates who are already receiving morphine as part of their standard of care. This approach
is successfully utilized in several 'POPS' studies (Pediatric Opportunistic Pharmacokinetic
Studies as part of Pharmacokinetics of Understudied Drugs Administered to Children per
Standard of Care program) conducted by the Pediatric Trials Network (http://pediatric
trials.org/).
Analysis Plan and Sample Size:
Primary clinical outcomes will be a comparison of pre-implementation compared with
post-implementation amounts of morphine given, as measured by number of PRN medications
given, area under the morphine concentration time curve, and cumulative amount of morphine
exposure above target concentration. Secondary outcomes will include an evaluation of
usability of the application using the System Usability Scale, indicating the extent to which
the tool is being used by those who have access and the extent to which it is effectively
incorporated into rounds to provide effective and safe analgesia for neonates with
effectiveness, efficiency, and satisfaction. After the initial development period, we will
collect data obtained from 200 neonates for a minimum of 18 months for analysis of both the
process and clinical outcomes.
Aim 2. Characterize the morphine exposure-response relationship by prospective evaluation of
dose requirements, morphine concentration, and pain parameters using PK and PD modeling.
The investigators will use validated approaches that have been supported by the U.S. Food and
Drug Administration and European Medicines Agency to develop a population PK/PD model using
nonlinear mixed effect analysis based on plasma concentrations of morphine and pain and
sedation assessment scores and vital sign trends (PD data) in relation to the clinical
procedure of study data enriched with retrospectively collected data. This methodology not
only allows one to estimate the "typical" pharmacokinetic and pharmacodynamic profile for the
population but also will characterize between and within PK variability for each patient over
time. Through a hierarchical modeling process, clinical characteristics can be identified to
help account for some of the observed variabilities and ultimately result in improved patient
specific dosing. This approach is particularly useful in identifying age related effects and
given the general sparseness of blood samples, the population approach is well suited for
studying pharmacokinetics and pharmacodynamics in pediatric populations. The model will
include a description of the maturation of morphine metabolism and clearance based on
postmenstrual age and time after birth as described in the literature. Model development and
validation will be performed according to good modeling practices.
Aim 3. Evaluate generalizability of the precision dosing platform by extending the platform
to include a synergistic medication, midazolam.
Development of midazolam module:
The NeoRelief decision support application is a modular platform developed to be extended to
other frequently used medications in the NICU such as midazolam. Published midazolam PK
models will will be coded in and serve as the starting point for a fully functional decision
support tool for precision dosing of midazolam. This process will be supported by the CCHMC
IS team who integrated systems specifications and interphase requirements for secure data
exchange between Epic and the morphine decision support platform.
Analysis Plan and Sample Size The evaluation plan and measures will be the same as those
enumerated for Specific Aim 1; (a) technical analytics including usage rates, time spent in
the application, accessibility; (b) user feedback and usability testing; (c) clinical
outcomes including doses of medication given, PRN doses administered, and cumulative dosing
measurements. After the initial development period, the investigators will collect data
obtained from 50 neonates for a minimum of 18 months for analysis of both the process and
clinical outcomes.
