ASPIRE: A Study Promoting Critical Illness Recovery in the Elderly
Phase: NA
Conditions: Acute Respiratory Distress Syndrome, Critical Illness, Critical Care
Sponsor: Wake Forest University Health Sciences

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Official Title:  ASPIRE: A Study Promoting Critical Illness Recovery in the 
Elderly   
NCT02963558 
IRB-Approved:  3/21/2023 
 

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ASPIRE: A Study Promoting Critical Illness Recovery in the Elderly 
 
Principal Investigator: 
D. Clark Files, MD 
 
Co-investigator(s): 
Michael Berry, PhD 
 
Sponsor or funding source: 
Wake Forest University Translational Science Center 
Wake Forest University Pepper Center 
Wake Forest University Critical Illness Injury and Recovery Research Center 
Wake Forest Center for Diabetes, Obesity, and Metabolism 
Departmental Start-Up Funds 
Ri, LLC (providing equipment only) 
NIA 1R03AG060076 - 01A1 
 
Background, Rationale and Context 
Advances in the care of critically ill patients have led to increased survivorship. However, survivors of 
critical illness are faced with a variety of short- and long-term complications, the most notable of which 
is intensive care unit acquired neuromuscular weakness (ICUAW).1 Older patients have a higher 
incidence of acquiring a critical illness, and muscle wasting in this population appears more severe.2,3 
Though we and others have shown that exercise administered during an intensive care unit (ICU) stay 
(early rehabilitation) can attenuate the severity of ICUAW,4,5 not all studies of rehabilitation have yielded 
positive outcomes.6,7  
 
Both pre-clinical animal studies from our lab and clinical studies suggest timing of rehabilitation may be 
key— EARLY (within 1-2 days) but not LATE (days 5 and beyond) initiation of ICU rehabilitation therapies 
in critically ill patients have generally led to improved functional outcomes.4,5,8-11 Unfortunately, 
significant barriers exist to the early implementation of ICU rehabilitation, most notably delirium and the 
use of sedating medications in the early phases of critical illness.12-14  
 
In this proposal, we will test the 
hypothesis that EARLY application of a 
novel early rehabilitation therapy in 
critically ill patients will improve 
functional outcomes, and change the 
functional trajectory of this population. 
We will perform a pilot study of early 
mobilization with a cycle ergometer 
(MOTOmed, see Figure 1) and translate 
into humans the pre-clinical 
mechanisms that may mediate the 
effects of early mobility. 
 
  
 
Figure 1: Use of a MOTOmed in a mechanically ventilated patient 

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Objectives 
1) To assess the feasibility of the 
application of a novel ICU 
early rehabilitation 
intervention.  
2) To obtain preliminary data to 
estimate the treatment effect 
size. This will allow power 
calculations for a larger, NIH-
funded clinical trial.  
3) To understand if the 
application of a novel early 
ICU rehabilitation intervention 
attenuates the loss of muscle 
mass over time through 
inhibition of the E3 ubiquitin 
ligase muscle ring finger 1 
protein.  
4)  To determine the effects of 
exercise on energy utilization, 
mitochondrial function, and 
CPT-1 activity. 
5) To determine the effects of 
the early ICU rehabilitation 
intervention on muscle mass.  
6) To determine the effect of the early ICU rehabilitation intervention on quality of life in critically ill 
older adults. 
 
Methods and Measures 
Design: 
Single-center randomized controlled pilot/phase II trial of a novel ICU early rehabilitation intervention.  
 
Setting: 
Wake Forest Baptist Medical Center Intensive Care Unit 
 
Subject selection criteria: 
Older adults with age ≥55 years old who are critically ill with acute hypoxic respiratory failure requiring 
mechanical ventilation with an expected duration of ≥3 days. 
 
• 
Inclusion Criteria 
 
Age ≥55 years old (Rationale: Older patients have a higher incidence of acquiring a critical illness, 
and muscle wasting in this population appears more severe. Therefore, this intervention may be most 
effective in this population.) 
 
Admission to a Wake Forest Baptist Medical Center Intensive Care Unit 
 
Acute Hypoxic respiratory failure on mechanical ventilation (MV) for <48 hours with a P:F ratio of 
<300 (or equivalent S:F ratio) with expected MV for at least 24 more hours 
Aim 4: 
Quality of Life
Aim 3: 
Mechanistic 
Outcomes, Muscle
Aim 2: 
Clinical Outcomes
Aim 1: 
Feasibility
30 older acute respiratory failure patients 
requiring mechanical ventilation
21 Patients 
Intervention Arm:
Passive Cycler +
Early Exercise
Feasibility
Physical Function
Muscle 
Ultrasound
SF -36
21 Patients 
Control Arm: 
Standard of Care
Feasibility
Physical Function
Muscle 
Ultrasound
SF-36
Figure 2:  
Flow Diagram of Study 

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Previously Functional (over past 3 months, as reported by proxy): Physical Function: Able to walk 4 
m (with or without assistive device)  
 
• 
Exclusion Criteria 
 
Neuromuscular Disease 
 
Cardiopulmonary Arrest with return of spontaneous circulation <6 hrs  
 
Palliative Goals of Care; withholding life-sustaining therapy 
 
Raised Intracranial Pressure (>20 mm Hg) 
BMI>45; absolute weight >= 150 kg 
Inability to cycle (including absent limbs, body length <1.5m, body habitus not fitting the cycle, 
inflammatory arthritis, significant joint problems including inability to bend arms/legs; pelvic and/or 
lower extremity fracture, lower extremity vascular bypass surgery) 
Pregnancy 
Use of continuous neuromuscular blockade 
Temporary Pacemaker or Swan Ganz catheter or femoral ECMO catheter/IABP 
Rhabdomyolysis with most recent CK >5000  
Clinical Diagnosis of Dementia on Medication 
Moribund 
Possible Exclusion: If the patient is on spine precautions, a discussion with the spine team will be 
necessary to determine eligibility for this study 
 
Sample Size 
 
We will randomize 21 subjects to the intervention group (novel ICU early rehabilitation) and 21 
subjects to the control group. This sample size is based on the fact that this is a pilot proposal and that 
we want to optimize study procedures. We also have preliminary data which shows that this sample size 
might be large enough to detect a difference between groups based on SPPB at ICU discharge.  
 
The primary analysis of the phase II part of the study is to compare SPPB at ICU discharge between the 
two groups using analysis of covariance (ANCOVA), adjusted for age, sex, and BMI. Under our 
assumptions of attrition (estimated at 15%) and mortality (SPPB=0 if patient has passed), with the 
current sample size (n=42), we will be able to detect an effect size of 0.98 or higher in the SPPB at ICU 
discharge with a power of 81% and a two-sided significance level of 0.05. This effect size is based on our 
pilot data and corresponds with the known minimal clinically important difference in SPPB of 0.5-1.3.15,16 
 
Interventions and Interactions 
We will randomize patients to intervention or control groups. Patients will receive therapies according 
to their group assignment until hospital discharge or day 14, whichever comes first.  
 
The intervention group will receive in-bed cycle ergometry within 48 hours of randomization if safety 
criteria (below) are met. In-bed cycle ergometry has been shown to be safe and feasible in the critically 
ill and is FDA-approved for use in this population.8,17-19 Subjects enrolled in the intervention arm will be 
screened at least 5 days per week to evaluate if they meet pre-defined safety criteria based on other 
studies of early mobilization and cycling in the ICU (see Table 1).4,5,8,17-20 Patients who meet the safety 
criteria will be positioned in the semi-recumbent position for cycling as per ICU guidelines. The cycler 
will provide 3 different possible modes of cycling—passive, active-assisted, and active. We will start with 
passive cycling and the patient may progress to active-assisted and active cycling. The goal duration of 
cycling will be 30 minutes. Subjects will receive in-bed cycling at least 5 times per week for the duration 

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of the ICU stay or until day 14, whichever comes first. During cycling and therapy sessions, study staff 
will also complete a case report form noting vital signs, level of mobilization, and other safety measures.  
 
We have updated our safety criteria based on other completed and ongoing cycle trials in the critically ill 
(NCT03021902 and NCT03471247 and NCT02377830.) See table below.  
 
 
 
 
In addition to cycling, the intervention arm will receive early physical therapy. This physical therapy (PT) 
will be performed according to a protocol of additional ICU and hospital-administered rehabilitation 
strategies previously developed in the Wake Forest MICU.4 Patients will receive 30 minutes of PT at least 
5 times per week when they are conscious. If unconscious (as in Level 1 below), then they will only 
receive passive range of motion (PROM) for 10 repetitions per body part daily. Once conscious, subjects 
will progress through the different levels of PT with an emphasis on ambulation.  
 
Therapy for the intervention arm patients will continue while on the floor. Outpatient therapy will be 
provided at the discretion of the patient’s treating physicians.  
 
 
Daily Exemption Criteria 
In-Session Stopping Criteria 
Neurologic 
Criteria 
• Uncontrolled Pain 
• Severe Agitation with a RASS +3 or +4 
• Severe Agitation with a RASS +3 or +4 
Respiratory 
Criteria 
• PEEP >15 
• FIO2 >80% 
• Unplanned Extubation 
• Sustained O2 desaturation <85% 
• Marked vent asynchrony 
Circulatory 
Criteria 
• An increase in vasopressor/inotrope by >5 
mcg/min in past 2 hrs 
• Levophed >50 mcg/min to maintain goal 
MAP 
• Active myocardial ischemia 
• Unstable or uncontrolled arrhythmia 
• Sustained symptomatic bradycardia (HR<40), 
tachycardia (HR>140), hypotension 
(MAP<60), or hypertension (MAP >130) 
• Concern for myocardial ischemia 
• New unstable or uncontrolled arrhythmia 
Other Criteria 
• Change in goals of care to comfort 
• Team perceives therapy to be 
inappropriate (eg new hemorrhage, new 
wound) 
• Patient Refusal 
• Catheter or tube dislodgement 
• Team, subject, or surrogate request 
termination of session 

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The control group will receive usual care physical therapy as ordered by the treating team both in the 
ICU and on the floor through hospital discharge. These subjects will also receive therapy as outpatients 
only as ordered by their regular physicians.  
 
Outcome Measure(s) 
1) To assess the feasibility of the application of a novel ICU early rehabilitation intervention.  
a. Primary Outcome for the pilot phase: Feasibility will be assessed by quantifying the ability to 
apply the MOTOmed device for at least a 15-minute session within 48 hours of 
randomization and meeting safety criteria.  
2) To obtain preliminary data to estimate the treatment effect size. This will allow power calculations 
for a larger, NIH-funded clinical trial.  
a. Short Physical Performance Battery (SPPB). We will measure SPPB at ICU and hospital 
discharge. Our primary outcome for the phase II study will be SPPB at ICU discharge.  
b. Handgrip strength and dynamometry at ICU discharge and hospital discharge. ICU length of 
stay, Hospital length of stay will also be measured. 
c. Healthcare utilization (ED visits, re-admissions) at 1, 3, and 6 months 
d. Ventilator free days at 28 days. 
e. Mortality at ICU discharge, hospital discharge, and 3 and 6 months 
f. 
Short Form-36 (SF-36)  at hospital discharge (in-person) and 3 and 6 months (by phone) 
3) To understand if the application of a novel early ICU rehabilitation intervention attenuates the loss 
of muscle mass over time through inhibition of the E3 ubiquitin ligase muscle ring finger 1 protein.  
a. Serial Skeletal Muscle Ultrasounds at days 0, 3, 5, ICU discharge, hospital discharge  
Muscle thickness, size and echogenicity in the vastus and the rectus femoris muscles 
b. Serial Plasma at days 0, 1, 3, and 5 and ICU and hospital discharge 
i. Plasma acylcarnitine profile 
ii. Will be banked for future studies 
c. Blood on 1st day of exercise (for 5 intervention patients only) will be evaluated for leukocyte 
kinetics in response to exercise (exploratory analysis) based on animal data. This is 
completed. 

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4) Pilot study: To determine the effects of exercise on energy utilization, mitochondrial function, and 
CPT-1 activity. Phase II: To determine the effects of exercise on energy utilization. 
a. Continuous non-invasive CO2 monitoring, day 0 through day 5 
b. Accelerometer activity monitor, day 0 through 2 weeks post-discharge. 
c. Nutritional Assessments, blood sugar levels, day 0 through ICU discharge 
 
 
Updated Testing Battery:  
 
 
NB—Inpatient assessments may be completed up to 1 day before or after the specified time point, and 
may be carried over to another assessment.  Outpatient assessments may be completed up to 2 weeks 
before or after the specified time point. Muscle biopsies may be performed up to 1 day before or 2 days 
after the specified time point.  
 
Data Collection for demographics and baseline information: Demographic Information will be obtained 
on all patients. Additionally, the Acute Physiology and Chronic Health Evaluation (APACHE), Charlson 
index, and the comorbidity indices will be calculated. Other variables which will be collected will include 
medications and information about ICU and hospital stays.  
 
Muscle ultrasounds will be completed per protocol with standard views required to examine the size 
and echogenicity of patient muscles. Gel will be applied to the skin, the ultrasound probe will be placed 
on the gel, and then with minimal pressure, the required images will be obtained. A Sonosite ultrasound 
machine will be used. Bony landmarks will confirm that the probe is placed perpendicular to the muscle. 
Images will be saved on a laptop computer and then analyzed with Image J software.  
 
 
 
 
TABLE 5:  
TESTING BATTERY 
Day 
0 
Day 
1 
Day 
3 
Day 
5 
ICU 
D/C 
Hosp 
D/C 
Phone: 3 
months 
Phone: 6 
months 
Aim 1: Physical Function: 
  Feasibility 
  MAT-sf 
  SPPB 
  Handgrip/ quad strength 
MoCA / MoCA Blind 
 
X 
X 
 
X 
 
 
X 
 
X 
 
X 
X 
X* 
X 
X 
 
X 
X 
X 
X 
X 
 
X 
 
 
 
X 
 
X 
 
 
 
X 
Aim 2 Muscle Mass: 
  Ultrasound 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
 
Aim 3: Quality of Life: 
  SF-36 
 
 
 
 
 
 
 
X 
 
X 
 
X 
Exploratory Outcomes:  
  ICU LOS 
  Hospital LOS 
  Vent-Free Days (28) 
  Healthcare Utilization 
  Mortality 
  Blood 
  Energy 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
 
 
 
X 
X 
 
 

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The Short Physical Performance Battery (SPPB) is based on timed measures of standing balance, walking 
speed, and ability to rise from a chair. Each measure is assigned a score ranging from 0 to 4, with a total 
possible summary score of 12. The SPPB was developed for functional evaluation of the geriatric 
population. Given the target population of this study, this is an ideal instrument to measure physical 
function in this cohort.  
 
Handgrip will be assessed with a Jamar hand-held dynamometer. Three trials with brief pauses will be 
performed for each hand. A recording of hand dominancy will also be made.  
 
Skeletal muscle strength will be measured in the lower extremities. An electronic strength dynamometer 
(MicroFET 2MT Dynamometer, Hoggan Health Industries, Salt Lake City, UT) will be used to collect 
strength measures of the ankle and knee, bilaterally. Three trials with brief pauses will be performed for 
each muscle group. The best performance of three trials will be selected for each side. 
 
Non-invasive continuous volumetric C02 (vC02) will be performed using either a NM3 device (Phillips-
Respironics) or ventilator capable of vC02 measurements.  Daily energy expenditure (divided into 12 
hour segments) will be calculated using the formula validated by Stapel et al.  vC02 measurements will 
not be used for clinical decision making.  The use of NM3 device poses minimal harm to enrolled 
patients.  
 
The activity monitors will be given to the patients when enrolled in the study to wear throughout their 
hospitalization. Patients will be asked to wear the accelerometer and return it  in with a pre-paid 
envelope.  
 
Health related quality of life will be assessed using the Short Form-36.  The SF-36 is a self-reported 
generic measure of health related quality of life.  It consists of 36 items which can be used to provide 
summary measures of physical and mental health and eight distinct dimensions of health. 
 
The Montreal Cognitive Assessment (MoCA) and the MoCA- BLIND will be used to measure cognitive 
status. The MoCA and the MoCA-BLIND are validated tools of 22-30 questions which assesses: short-
term memory recall, visuospatial abilities, executive function, attention, concentration, and working 
memory, language, conceptual thinking, calculations, and orientation to time and place. They are highly 
sensitive and specific to detect mild cognitive impairment.  
 
The Mobility Assessment Tool short form (MAT-sf) is a video animated tool for assessing self-perception 
of mobility. Items consist of a video and a corresponding measurement item. The video depicts a 
wooden mannequin performing a wide range of physical activities and the measurement item consists 
of a question about the participant’s ability to perform the task, measured on a discrete scale.  
 
Healthcare utilization and mortality will be determined through a variety of mechanisms including a 
review of the electronic medical record, phone calls to patients/ families/ contacts provided at the start 
of the study, and a query of the NC State Death Index.   
 
Analytical Plan 
Phase I pilot study: 
Given that this is a pilot study, all analyses other than the feasibility assessment and basic descriptive 
statistics will be performed solely to inform a larger trial. Power calculations will not be utilized for this 
study given it is a pilot study.  

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We have a growing ICU population over the past 5 years. In 2013 alone, we had >1300 older adults 
admitted to just the MICU. Thus, we should have a large population of patients on which to draw from 
for enrolment in the study.  
 
Patient demographics will be evaluated with descriptive statistics. The objectives will be evaluated as 
described below. 
 
1) The feasibility of compliance to the application of the novel ICU early rehabilitation intervention will 
be assessed by the number of patients in the intervention arm out of the total intervention patients 
(10) who are able to undergo a 15 minute cycling session within the first 48 hours of randomization 
and meeting safety criteria. 
2) SPPB, handgrip strength/dynamometry, calorimetry, ICU and hospital lengths of stay, healthcare 
utilization (SPPB), ventilator-free days, mortality, and SF-36 and MoCA scores will all be analyzed 
with descriptive statistics. Tests for trend will be evaluated and adjusted analyses will also be 
performed. Analysis of co-variance will be used, adjusted for age, gender, and BMI and other 
adjusted analyses will be performed as necessary. We will also explore the longitudinal effect of the 
intervention with linear mixed effect models. 
3) And 4)   Muscle ultrasound measures, skeletal muscle biopsy measures, and plasma analyses will 
also be analyzed with descriptive statistics, tests for trend including with linear mixed effect models , 
and adjusted analyses.  
 
In sum, results will be analyzed initially using descriptive statistics.  Comparison between groups will be 
done using chi square tests for proportions, and t-tests or ANOVA procedures for continuous variables.  
Regression analysis will be performed to identify independent outcome predictors.  Other inferential 
statistical analysis will be conducted as appropriate. 
 
Phase II: The primary analysis is to compare SPPB at ICU discharge between the two groups using 
analysis of covariance (ANCOVA), adjusted for age, gender, and BMI. Under our assumptions of attrition 
(estimated at 15%) and mortality (SPPB=0 if patient has passed), with the current sample size (n=42), we 
will be able to detect an effect size of 0.98 or higher in the SPPB at ICU discharge with a power of 81% 
and a two-sided significance level of 0.05. This effect size is based on our pilot data and corresponds 
with the known minimal clinically important difference in SPPB of 0.5-1.3.15,16 We will perform similar 
analyses for SPPB at hospital discharge and explore the longitudinal effect of the intervention, using 
linear mixed effect models to compare the trajectories of SPPB over time. We will analyze secondary 
outcomes including hand grip, quadriceps dynamometry, RF CSA and echogenicity, quadriceps depth, TA 
depth and echogenicity, and QOL in a similar fashion. For this study, the services of the Pepper Center 
Biostatistics and Research Information Systems Core will be used. 
 
Human Subjects Protection 
Please see attached document. 
 
Subject Recruitment Methods 
Our ICU research team will screen patients admitted to the ICU for inclusion/ exclusion criteria for entry 
into the study. We will only access necessary information (using a minimal amount of PHI) for screening 
through the electronic medical record. PHI necessary will include name, geographic information, dates, 
telephone number, medical record, and access to this information will be sought under a limited HIPAA 
waiver. All information will remain confidential in a password protected file on a password protected 

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computer. If deemed eligible, subjects (or their surrogates if unable to consent for themselves) will be 
approached for consent. If the patient/ surrogate does not consent for the study, the study team will 
maintain a record of those not enrolled which will be kept in a password protected file on a password 
protected computer. This record will be destroyed 3 years after study completion and publication. 
 
We will not differentially approach women or minorities for inclusion in this study. However, please 
note that given the small sample size of this project, we will likely have imbalances.  
 
Informed Consent 
Signed informed consent will be obtained from each subject or from a surrogate decision-maker. If a 
surrogate decision-maker is used for initial consent, then when the patient is mentally able to consent 
for him/herself, he/she will be re-approached by the study coordinator or investigators for consent. All 
consents will take place in the ICU.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting only information needed to assess study outcomes, 
minimizing to the fullest extent possible the collection of any information that could directly identify 
subjects, and maintaining all study information in a secure manner.  To help ensure subject privacy and 
confidentiality, only a unique study identifier will appear on the data collection form.  Any collected 
patient identifying information corresponding to the unique study identifier will be maintained on a 
linkage file, stored separately from the data.  The linkage file will be kept secure, with access limited to 
designated study personnel.  We will input data into the RedCAP web based data entry system as it is 
highly secure and is regularly backed up. Following data collection subject identifying information will be 
destroyed three years after publication of the study, consistent with data validation and study design, 
producing an anonymous analytical data set.  Data access will be limited to study staff.  Data and records 
will be kept locked and secured, with any computer data password protected.  No reference to any 
individual participant will appear in reports, presentations, or publications that may arise from the 
study. 
 
Data and Safety Monitoring 
The principal investigator will be responsible for the overall monitoring of the data and safety of study 
participants.  The principal investigator will be assisted by other members of the study staff. 
 
Additionally, a Data and Safety Monitoring Board will be convened by the PI. This DSMB will monitor all 
serious/unexpected adverse events as well.  
 
Reporting of Unanticipated Problems, Adverse Events or Deviations 
Any unanticipated problems, serious and unexpected adverse events, deviations or protocol changes 
will be promptly reported by the principal investigator or designated member of the research team to 
the IRB and sponsor or appropriate government agency if appropriate. 
 
Appendix 
Copies of each questionnaire or surveys that will be used 
Consent form 
 
 

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