Maximizing trEatment of Neurological Dysfunction Using INtravenous Guanfacine Study
Phase: PHASE2
Conditions: Critical Illness, Delirium, Cognitive Impairment
Sponsor: Vanderbilt University Medical Center

Maximizing trEatment of Neurological Dysfunction using 
INtravenous Guanfacine (MENDING) study  
 
NCT 04742673 
 
February 7, 2024 
 

Title 
Maximizing trEatment of Neurological Dysfunction using 
INtravenous Guanfacine (MENDING): A Randomized Placebo-
Controlled Trial 
Trial Registration 
https://clinicaltrials.gov/study/NCT04742673  
Date 
2/7/2024 
SAP Version 
1.0 
Principal Investigator 
Christopher G. Hughes 
Biostatisticians 
Rameela Raman, Onur M. Orun 
 
INTRODUCTION 
 
This document serves as the Statistical Analysis Plan (SAP) for Aims 1 and 2 of the Maximizing 
trEatment of Neurological Dysfunction using INtravenous Guanfacine (MENDING) Trial. It 
accompanies version 1.5 of the protocol (dated 9/12/2023). This SAP has been completed prior 
to the completion of enrollment, unblinding of data, and the analyses of the outcomes. 
 
1. METHODS AND DESIGN 
 
1.1. TRIAL DESIGN AND AIMS 
 
The MENDING trial is a phase II proof-of-concept trial of IV guanfacine vs. placebo for the 
treatment of critical illness delirium. The aims of the trial are the following: 
Aim 1: To determine whether IV guanfacine twice a day will increase the number of days 
alive without delirium and coma (delirium/coma-free days, DCFDs) over 14 days 
relative to placebo. 
Aim 2: To evaluate whether IV guanfacine twice a day will increase days alive and free of 
mechanical ventilation (ventilator-free days, VFDs) and days alive and free of the ICU 
(ICU-free days, IFDs) over 28 days relative to placebo.  
 
1.2. RANDOMIZATION AND BLINDING 
 
The trial aims to randomize 50 patients with delirium in the ICU in a 1:1 ratio to IV 
guanfacine or placebo. A computer-generated randomization scheme (with permuted block 
sizes) was created by the study’s primary biostatistician and uploaded directly into 
REDCap’s randomization module [1-2]. Investigators, patients, and clinicians will be blinded 
for the duration of the study until the database is locked. 
 
1.3. POWER ANALYSIS AND SAMPLE SIZE 
 
Prior to beginning enrollment, our goal was to enroll and randomize 100 participants. We 
estimate that the participants in the placebo group will have 6.9±5.2 delirium/coma-free days 
(DCFDs) during the 14-day interventional study period based on the results from the 
recently completed Maximizing the Efficacy of Sedation and Reducing Neurological 
Dysfunction and Mortality in Septic Patients (MENDS2) study that used similar entry criteria 
[3]. Enrolling 100 patients would provide us at least 80% power to detect a 3 DCFDs 

difference between the treatment groups over 14-day period for Aim 1. For Aim 2, we 
estimate that the participants in the placebo group will have 15.4±10.9 ventilator-free days 
(VFDs) and 13±10 ICU-free days (IFDs) based on the results from our MENDS2 study. 
Enrolling 100 patients would provide us at least 80% power to detect a 6 VFDs and 5.6 IFDs 
difference between the treatment groups over 28-day period. 
 
Due to low enrollment and, given that this is a phase II proof-of-concept trial to guide safety 
and preliminary efficacy for future work, our final enrollment target was reduced from 100 to 
50 with approval from the National Institute of Health and the Data and Safety Monitoring 
Board. 
 
By analyzing 50 patients, we will have 80% power to detect a difference of 4.2 DCFDs over 
14 days between the IV guanfacine and placebo groups. By analyzing 50 patients, we will 
have 80% power to detect a difference of 8.8 VFDs and 8.1 IFDs over 28 days between the 
IV guanfacine and placebo groups. 
 
2. OUTCOMES 
 
2.1. PRIMARY OUTCOME 
 
The primary outcome is delirium/coma-free days (number of days alive without delirium or 
coma) for 14 days starting on the day of randomization. 
 
2.2. SECONDARY OUTCOMES 
 
The secondary outcomes are: 
 
• 
Ventilator-free days (number of days alive and free of mechanical ventilation) for 
28 days starting on the day of randomization. 
• 
Intensive care unit (ICU)-free days (number of days alive and free of ICU) for 28 
days starting on the day of randomization. 
 
For VFDs, both invasive and non-invasive ventilation will be taken into account. To account for 
terminal extubation for comfort care measures, successful ventilator (invasive or non-invasive) 
discontinuation will be defined as being alive and free of ventilation for 48 hours following 
discontinuation. For example, if a patient was discontinued from MV and ventilation was initiated 
again within the next 48 hours or the patient died within the next 48 hours, then the time (<48 
hours) that was off ventilation did not count as a ventilator-free day. Similarly, for ICU-free days, 
successful ICU discharge will be defined as being alive and free of ICU stay for 48 hours 
following ICU discharge. 
 
2.3. EXPLORATORY OUTCOMES 
 
The exploratory outcomes are: 
 
1. Hospital-free days (number of days alive and free of hospital) for 28 days starting 
on the day of randomization. 
2. 90-day mortality starting on the day of randomization. 
 
For hospital-free days, successful hospital discharge will be defined as being alive and free of 
hospital stay for 48 hours following hospital discharge. 

 
 
2.4. DESCRIPTIVE OUTCOMES 
 
Among others, the following outcomes will be reported as descriptive statistics. 
 
1. Co-administration of sedatives, analgesics, and antipsychotics (frequency and 
quantity of administration) for 14 days starting on the day of randomization.  
2. Hypotension (refractory systolic blood pressure < 90 mm Hg or mean arterial 
blood pressure < 65 mm Hg despite ongoing ICU therapies) for 14 days starting 
on the day of randomization. 
3. Bradycardia (heart rate < 60 beats per minute despite ongoing ICU therapies) 
for 14 days starting on the day of randomization. 
4. Mental status (new, acute neurologic disturbances such as blurred vision, 
dizziness, weakness, or vertigo) for 14 days starting on the day of 
randomization. 
 
 
 
3. STATISTICAL ANALYSIS 
 
3.1.  STATISTICAL PRINCIPLES 
 
The statistical analyses for all the aims will be conducted as per this SAP and follow the 
statistical principles described below. 
 
Participant flow diagram of this trial will be reported as specified by the Consolidated 
Standards of Reporting Trials (CONSORT) 2010 guidelines [4]. The flow diagram will display 
all stages of the trial such as screening, exclusions, enrollment, randomization, death, and 
study withdrawal. 
 
Demographic information, clinical characteristics at baseline and study outcomes will be 
presented for each treatment group. Median and interquartile range (IQR) will be used for 
describing continuous variables, and frequency (%) will be used for describing categorical 
variables. 
 
No hypothesis testing for the differences in baseline characteristics between the treatment 
groups will be conducted as recommended by the CONSORT 2010 guidelines for reporting 
parallel group randomized clinical trials [4-5]. 
 
Statistical significance level will be set at 5% for all outcomes. 95% confidence intervals will 
be reported with all effect estimates. No multiple comparison adjustments will be made for 
secondary and exploratory outcomes following the standard practice of analyzing multiple, 
prospective clinical trial outcomes [6-9]. No subgroup analyses will be conducted. 
 
Missing data will be imputed, and the imputation process will be reported in detail. Since the 
percentage of missing data is anticipated to be lower than 5%, single imputation is planned 
to be used. 
 
3.2. ANALYSIS POPULATION 
 

Analysis population will be based on the modified intent-to-treat (ITT) principle for all 
outcomes. The analysis cohort will include patients who were randomized and received 
study drug for all the primary, secondary and exploratory outcomes unless otherwise 
specified in this SAP. 
 
3.3. ANALYSIS METHODS AND MODEL ASSUMPTIONS 
 
All outcomes will be analyzed using regression models. Since this is a phase II proof-of-
concept randomized controlled trial, unadjusted analyses will be the primary analyses, 
where the models will only have the treatment variable and will not be adjusted for any 
covariates. 
 
Proportional odds logistic regression (POLR) will be used for modeling skewed continuous 
outcomes [10-11]. Proportional odds assumptions will be checked graphically using multiple 
cutoffs of the outcome, i.e., binary logistic regression models will be fitted using different 
cutoffs of the outcome, and the log odds ratios (estimated coefficients) will be plotted against 
cutoffs to check proportionality assumption [10]. Odds ratios along with 95% confidence 
intervals will be reported for POLR models. 
 
Simple linear regression will be used for continuous outcomes that are normally distributed 
and satisfy the other assumptions. Assumptions will be checked graphically using residuals 
versus fitted values plots and quantile-quantile plots. Regression coefficients along with 95% 
confidence intervals will be reported for linear regression. 
 
For 90-day mortality, Kaplan-Meier survival curve stratified by the treatment groups will be 
reported. Patients alive at 90-day will be censored at 90-day. Patients whose death 
information is unknown will be censored at their last known date alive. 
 
Adjusted analyses will be conducted as sensitivity analyses. For adjusted analyses, all 
outcomes will be modeled using multivariable regression methods adjusting for the following 
covariates: age and severity of illness (measured by SOFA score) at randomization. If we 
have sufficient degrees of freedom in the model, interaction of age and treatment will be 
evaluated using an interaction term in the model. Otherwise, descriptive statistics will be 
generated by subgroups. For multivariable regression models, depending on the distribution 
of the variable, non-linear relationships between the outcome and the continuous covariates 
will be incorporated into the statistical models using restricted cubic splines with 3 knots 
when appropriate. 
 
For the sensitivity analyses, redundancy analysis will be performed before modeling using 
an adjusted R2 cutoff of 0.7 to evaluate for multicollinearity. Covariates that are highly 
correlated will be dropped from the model based on the rank order specified above. If the 
model is overfit, covariates will be reduced based on the rank order listed above. 
 
4. SOFTWARE 
 
Statistical software R version 4.2.3 (or above) will be used for all analyses [12]. 
 
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