Breath Synchronized Abdominal Muscle Stimulation to Facilitate Ventilator Weaning: a Pilot
Conditions: Electric Stimulation, Respiration, Artificial, Ventilator Weaning
Sponsor: Liberate Medical



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LIBERATE MEDICAL, LLC 
 
Clinical Research Protocol 
 
BREATH SYNCHRONIZED ABDOMINAL MUSCLE STIMULATION TO FACILITATE 
VENTILATOR WEANING: A PILOT STUDY  
 
Protocol Number: 
VF-KINDRED-01 
Version Date: 
8 August 2016 
Investigational Product: 
VentFree 
IDE Number: 
Non-significant risk device 
Sponsor: 
Liberate Medical, LLC 
6400 Westwind Way, Suite A 
Crestwood, KY, 40014 
Funding Organization: 
Liberate Medical, LLC 
Principal Investigator: 
Name:  
Dr. Lucas Abraham 
Telephone: 
(502) 587-8000 
Fax: 
 
(502) 583-8001 
 
Medical Monitor: 
Name:  
Dr. Franco Laghi 
Telephone: 
(708) 528-1807 
Email:  
Franco.Laghi@vs.gov 
 
 
Approval: 
 
 
 
PI or Sponsor Signature (Name and Title)  
 
Date 
This confidential information about an investigational product is provided for the exclusive 
use of investigators of this product and is participant to recall at any time.  The information in 
this document may not be disclosed unless federal or state law or regulations require such 
disclosure.  Participant to the foregoing, this information may be disclosed only to those 
persons involved in the study who have a need to know, with the obligation not to further 
disseminate this information.   
 
 
 

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PROTOCOL AGREEMENT 
 
I have read the protocol specified below. In my formal capacity as Investigator, my 
duties include ensuring the safety of the study participants enrolled under my 
supervision and providing Liberate Medical, LLC with complete and timely 
information, as outlined in the protocol.  It is understood that all information 
pertaining to the study will be held strictly confidential and that this confidentiality 
requirement applies to all study staff at this site. Furthermore, on behalf of the study 
staff and myself, I agree to maintain the procedures required to carry out the study 
in accordance with accepted GCP principles and to abide by the terms of this 
protocol. 
 
Protocol Number:  VF-KINDRED-01 
 
Protocol Title:  Breath synchronized Abdominal Muscle Stimulation to Facilitate 
Ventilator Weaning: A Pilot Study 
 
Protocol Date:  8th August 2016 
 
 
 
 
Investigator Signature  
 
Date 
Dr. Lucas Abraham, Pulmonary Physician  
Print Name and Title 
Site Name 
Kindred Hospital – Louisville 
Address 
1313 St. Anthony Place 
 
Louisville, KY, 40204 
 
 
 
 
Phone Number (502) 587-8000 
 
 
 
 

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Table of Contents 
1 LIST OF ABBREVIATIONS 
6 
2 PROTOCOL SYNOPSIS 
7 
3 BACKGROUND 
11 
3.1 THE HEALTHCARE PROBLEM 
11 
3.2 WHY DO PATIENTS FAIL TO WEAN? 
11 
3.3 CURRENT STANDARD OF CARE 
12 
3.4 UNMET MEDICAL NEED 
12 
4 VENTFREE 
12 
4.1 STUDY DEVICE 
13 
4.2 OVERVIEW OF CLINICAL STUDIES 
14 
5 OBJECTIVES OF THE CLINICAL INVESTIGATION 
15 
6 STUDY DESIGN 
15 
7 OUTCOME MEASURES 
16 
7.1 PRIMARY OUTCOME MEASURES 
16 
7.2 SECONDARY OUTCOME MEASURES 
16 
8 PARTICIPANT SELECTION 
17 
8.1 PARTICIPANT POPULATION 
17 
8.2 INCLUSION CRITERIA 
17 
8.3 EXCLUSION CRITERIA 
17 
8.4 PATIENT RECRUITMENT 
18 
9 STUDY TREATMENTS 
18 
9.1 METHOD OF ASSIGNING PARTICIPANTS TO TREATMENT GROUPS 
18 
9.2 BLINDING 
18 
9.3 ACTIVE AND PLACEBO STUDY DEVICES 
19 
9.3.1 
ACTIVE STIMULATION DEVICE 
19 
9.3.2 
PLACEBO STIMULATION DEVICE 
19 
9.4 NUMBER OF STUDY DEVICES 
20 
9.5 PACKAGING AND LABELING OF THE STUDY DEVICES 
20 
9.6 DEVICE ADMINISTRATION 
20 
9.6.1 
ELECTRODE PLACEMENT 
20 
9.6.2 
DEVICE SETUP 
20 
9.6.3 
STIMULATION SESSION 
21 
9.7 DEVICE DEFICIENCY/FAILURE 
21 
10 APPARATUS 
21 
10.1 MOUTH PRESSURE METER 
21 
10.2 PEAK EXPIRATORY FLOW METER 
22 

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11 STUDY PROCEDURES 
22 
11.1 CONCOMITANT MEDICATIONS 
22 
11.2 DEMOGRAPHICS 
22 
11.3 MEDICAL HISTORY 
22 
11.4 PHYSICAL EXAMINATION 
22 
11.5 VITAL SIGNS 
22 
11.6 OXIMETRY 
22 
11.7 ACUTE PHYSIOLOGY AND CHRONIC HEALTH EVALUATION 
22 
11.8 EXPIRATORY FLOW LIMITATION 
22 
11.9 MAXIMUM EXPIRATORY PRESSURE AND MAXIMUM INSPIRATORY PRESSURE 
23 
11.10 THICKNESS OF THE ABDOMINAL WALL MUSCLES 
23 
11.11 THICKNESS OF THE DIAPHRAGM 
23 
11.12 COUGH PEAK FLOW 
23 
11.13 SENSATION OF STIMULATION 
23 
11.14 ADVERSE EVENTS 
23 
11.15 MEASURES OF TREATMENT COMPLIANCE 
23 
12 STUDY SCHEDULE 
23 
12.1 BASELINE VISIT - DAY 1 
24 
12.2 STIMULATION VISITS – DAYS 2 - 22 
24 
12.3 INTERMEDIATE VISIT – DAY 23 
24 
12.4 STIMULATION VISITS – DAYS 24 – 44 
24 
12.5 FINAL VISIT – DAY 45 
25 
12.6 EARLY WITHDRAWAL VISIT 
25 
13 ADVERSE EXPERIENCE REPORTING AND DOCUMENTATION 
25 
13.1 ADVERSE EVENTS 
25 
13.2 SERIOUS ADVERSE EXPERIENCES (SAE) 
26 
13.2.1 SERIOUS ADVERSE EXPERIENCE REPORTING 
27 
13.3 MEDICAL MONITORING 
27 
14 DISCONTINUATION AND REPLACEMENT OF PARTICIPANTS 
27 
14.1 WITHDRAWAL OF PARTICIPANTS FROM THE STUDY 
27 
12.3 REPLACEMENT OF PARTICIPANTS 
28 
15 PROTOCOL VIOLATIONS 
28 
16 PROTOCOL AMENDMENTS 
28 
17 STATISTICAL METHODS AND CONSIDERATIONS 
28 
17.1 SAMPLE SIZE 
29 
18 DATA COLLECTION, RETENTION AND MONITORING 
30 
18.1 DATA COLLECTION INSTRUMENTS 
30 
18.2 AVAILABILITY AND RETENTION OF INVESTIGATIONAL RECORDS 
30 
18.3 MONITORING 
30 
18.4 PARTICIPANT CONFIDENTIALITY 
30 

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19 STATEMENT OF COMPLIANCE 
31 
20 PUBLICATION POLICY 
31 
21 REFERENCES 
31 
22 APPENDIX A: SCHEDULE OF EVENTS 
33 
 
 
 

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1 List of Abbreviations 
 
AE 
Adverse event 
APACHE II 
Acute Physiology and Chronic Health Evaluation II 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
COPD 
Chronic obstructive pulmonary disease 
CPF 
Cough Peak Flow 
CRF 
Case report form 
ETCO2 
End-tidal carbon dioxide 
FDA 
Food and Drug Administration 
FEV1 
Forced Exhaled Volume in 1 second 
FVC 
Forced Vital Capacity 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
MAUDE 
Manufacturer and User Facility Device Experience 
MEP 
Maximum expiratory pressure 
MIP 
Maximum inspiratory pressure 
MV 
Mechanical ventilation 
NMES 
Neuromuscular electrical stimulation 
PEF 
Peak expiratory flow 
PI 
Principal Investigator 
PTPdi 
Pressure-time products of the diaphragm 
PTPga 
Pressure-time products of the gastric space 
SAE 
Serious adverse experience 
SBT 
Spontaneous breathing trial 
SCI 
Spinal Cord Injury 
SPO2 
Peripheral capillary oxygen saturation 
VAP 
Ventilator acquired pneumonia  
 
 

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2 Protocol Synopsis 
TITLE 
Breath synchronized Abdominal Muscle Stimulation to Facilitate 
Ventilator Weaning: A Pilot Study  
SPONSOR 
Liberate Medical, LLC 
FUNDING 
ORGANIZATION 
Liberate Medical, LLC 
NUMBER OF SITES 
1 
RATIONALE 
In the U.S. over 500,000 patients have difficulty weaning from 
mechanical ventilation every year. These patients cost the health 
care system $16 billion annually and have an increased risk of 
medical complications and morbidity. 
 
A major factor responsible for weaning failure is the imbalance 
between decreased respiratory muscle strength and excessive 
respiratory load. VentFree (Liberate Medical, LLC) is an 
investigational device that applies electrical stimulation to the 
abdominal muscles in synchrony with exhalation. This is 
hypothesized to improve the strength of the respiratory muscles. 
The long term goal of this project is to determine whether this 
approach can reduce the number of days taken for patients to 
wean from mechanical ventilation. 
STUDY DESIGN 
This is a single center, participant blinded randomized placebo 
controlled pilot trial. 
PRIMARY OBJECTIVE 
The primary objective of this study is to determine whether NMES 
applied to the abdominal wall muscles in synchrony with 
exhalation can increase the strength of the respiratory muscles in 
prolonged mechanical ventilation patients 
SECONDARY 
OBJECTIVES 
The secondary objectives of the study is to evaluate whether this 
intervention also affects: (1) the thickness of the abdominal wall 
muscles and the diaphragm, (2) functional respiratory 
measurements, and (3) weaning outcome 
NUMBER OF 
PARTICIPANTS 
Twenty six: 13 in the treatment arm and 13 in the control arm. 
PARTICIPANT 
SELECTION 
CRITERIA 
Inclusion Criteria:  
x Patients who have been mechanically ventilated for at least 
fourteen days. 
x Clinically stable: oxygen saturation > 90% with a fractional 
inspired oxygen ≤ 0.40, external PEEP ≤ 5 cm H2O, 
temperature ranging from 35.5 to 38.5Co, no intravenous 
administration of vasoactive agents.  
Exclusion Criteria:  

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x Patients in whom Neuromuscular Electrical Stimulation 
(NMES) does not elicit a palpable contraction of the 
abdominal muscles.  
x Patients with broken or irritated skin on the abdominal 
wall 
x Patients with a history of neuromuscular disease 
x Body Mass Index (BMI) > 35 kg/m2 
x Patients who are not medically stable 
x Patients with a pacemaker 
x Female patients who are pregnant  
x Patients under the age of 18 
x Patients who are expected to die within four weeks 
x Patients who are unable to follow verbal instructions 
x Patients with epilepsy  
x Patients with an abdominal wall hernia  
x Patients with anoxic encephalopathy 
x Patients with history of, or active, substance abuse 
ACTIVE DEVICE  
VentFree prototype (VF03) that delivers electrical stimulation 
pulses to the abdominal muscles during exhalation with a 
frequency of 30 Hz, a pulse width of 350 µs and 90% of the 
maximum current that the participant can tolerate. These 
stimulation parameters were selected to cause a tetanic 
(continuous) contraction of the abdominal muscles, without pain 
for the patient. Stimulation will be administered for  
30 minutes 2 times per day, 5 days per week, for 6 weeks; or until 
the patient is weaned from mechanical ventilation.  
CONTROL DEVICE 
Modified VentFree prototype (VF03) that delivers stimulation 
pulses to the abdominal muscles during exhalation with a 
frequency of 10 Hz, a pulse width of 100 µs and current set to 10 
mA. These stimulation parameters were chosen to cause a twitch 
contraction of the abdominal wall muscles. Stimulation will be 
administered for 30 minutes, 2 times per day, 5 days per week, for 
6 weeks; or until the patient is weaned from mechanical 
ventilation. 
DURATION OF 
PARTICIPANT 
PARTICIPATION AND 
DURATION OF STUDY 
Participants will participate in the study for up to 45 days. 
The total duration of the study is expected to be 6 months (4.5 
months for participant recruitment and 1.5 months for final 
participant follow-up). 
CONCOMMITANT 
MEDICATIONS 
No medications will be restricted as part of this study. 
EFFICACY 
EVALUATIONS 
• 
Sensation of stimulation experienced by the patient   
• 
Number of days taken to wean  

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• 
Time spent breathing without mechanical ventilation 
support 
• 
Respiratory muscle strength  
• 
Peak expiratory flow 
• 
Resting breathing parameters 
PRIMARY ENDPOINT 
x 
Maximum inspiratory and expiratory pressure 
SECONDARY 
ENDPOINTS 
x 
Thickness of the abdominal wall muscles  
x 
Thickness of the diaphragm 
x 
Weaning success 
x 
Number of days taken to wean 
x 
Time spent breathing without mechanical ventilation support 
x 
Cough peak flow 
x 
Resting breathing parameters  
x 
Adherence to the study protocol  
x 
Sensation of stimulation experienced by the patient 
x 
Adverse events 
STATISTICS 
Analysis Plan 
Only participants who fulfil the protocol in terms of eligibility, 
interventions and outcome assessment will be included in the 
statistical analysis. 
 
Study results will first undergo descriptive level statistical 
analyses. In the second level of analysis, we will quantify the 
magnitude to which abdominal NMES exhibits a protective effect 
using regression models.  
 
Weaning success will be compared between the study groups 
using Poisson regression. Kaplan Meier survival analysis will be 
used to compare the time to wean in both study groups. 
 
Adverse event rates will be coded by body system and MedDra 
classification term.  Adverse events will be tabulated by treatment 
group and will include the number of patients for whom the event 
occurred, the rate of occurrence, and the severity and relationship 
to study treatment.    
Rationale for Number 
of Participants 
This study is intended to be a pilot study that will be used to 
obtain initial data on the feasibility and safety of VentFree to 
assist in the process of ventilator weaning. The primary outcome 
of this study is the effect of abdominal NMES on respiratory  
muscle strength over time. There is currently no data in the 
literature to support a sample size calculation for this study. Given 
this constraint, in this pilot study a total of 24 participants was 
deemed adequate and is consistent with sample size 
recommendations in the literature.1 Allowing for a 10% drop out 
rate, a total of 26 participants will be recruited for this study. The 
data collected on the secondary endpoints will be used to 

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determine the participants needed for a future randomized 
controlled trial of the device on weaning outcome. 
 
 

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3 Background  
Approximately one million patients in the US are estimated to undergo mechanical 
ventilation from respiratory failure (MV) every year, resulting in an annual cost of 
$27 billion.2 Approximately seven hundred thousand of these patients have 
difficulty weaning from MV, with many requiring prolonged MV.3 In the US, the 
overall health-care cost of this latter group of patients is estimated to be more than 
$16 billion per year.4 Furthermore, patients requiring prolonged MV are susceptible 
to a wide range of secondary complications and have excess mortality.5,6 The 
current standard of care to wean patients requiring prolonged MV is to have them 
undergo daily spontaneous breathing trials (SBTs).7,8 These trials are carried out 
using a variety of strategies intended to progressively reduce the extent of MV 
support,7,8 while encouraging the patient to breathe on their own. These SBTs, 
which can last anywhere between days5 and months,7,8 aim to recondition the 
respiratory muscles, which are weakened during MV.9 However, in the most severe 
cases, patients may never wean from MV.10 There are currently only a limited 
number of interventions that can accelerate the process of weaning from MV. 
3.1 The Healthcare Problem 
The most common indications for MV, as derived from a study of more than 5000 
patients in 20 countries,11 are acute respiratory failure (69%), coma (17%), acute 
exacerbation of Chronic Obstructive Pulmonary Disease (COPD; 10%), asthma (2%), 
and neuromuscular disorders (2%). The objectives of MV are to improve gas 
exchange, relieve respiratory distress and permit lung and airway healing while 
avoiding complications. 12 Though potentially life-saving, MV can also cause life-
threatening complications including barotrauma, ventilator associated pneumonia 
(VAP), respiratory muscle atrophy, ventilator-associated lung injury and 
psychological complications such as depression. 12 Accordingly, it is imperative to 
wean patients from MV in the fastest time possible.12 
3.2 Why Do Patients Fail To Wean? 
In most patients, the primary pathophysiologic mechanism of weaning failure is an 
imbalance between an excessive respiratory load and reduced respiratory muscle 
strength (see Figure 1).13 Increased respiratory load can be caused by an increase in 
the stiffness and/or resistance of the respiratory system. 12 Increased stiffness can 
be the result of VAP, pulmonary edema and pulmonary fibrosis and increased 
resistance can be the result of endobronchial neoplastic pathologies, asthma and 
COPD, or by the process of weaning itself (either by the presence of the 
endotracheal tube or due to increased secretions following extubation).13 Reduced 
respiratory muscle strength can result from a combination of disuse 
atrophy/dysfunction, sepsis, polyneuropathy, as well as poor nutrition and 
medications.13 Strikingly, recent evidence has shown a 50% decrease in diaphragm 
muscle fiber cross sectional area after just 18 to 72 hours of controlled MV.14 

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3.3 Current Standard of Care 
A recent international symposium generated guidelines for weaning from MV. These 
guidelines state that active weaning from MV should commence when the pathology 
responsible for the institution of MV has been resolved and when the patients are 
clinically stable. 13 A weaning trial commonly consists of a period of completely 
unsupported breathing (e.g., T-tube trial) or a period of minimal ventilator support 
(e.g., pressure support ventilation). If the patient does well during the weaning trial 
(i.e. is able to comfortably breathe unassisted) he/she is extubated; otherwise, the 
patient resumes MV. 13   
When patients do not pass the first weaning trial, the potential mechanisms for 
weaning failure must be identified and addressed.13 In addition, the aforementioned 
guidelines suggest implementing daily SBTs, during which the work of breathing 
accomplished by the ventilator is progressively reduced, and thus, the respiratory 
muscles weakened during the preceding pre-weaning period of MV are 
reconditioned.9,15  
3.4 Unmet Medical Need  
To date, a daily SBT is the only intervention used in the weaning of prolonged MV 
patients. Unfortunately, this process can last anywhere between days5 and 
months.7,8 In the most severe cases, patients never wean from MV.10 Therefore, 
novel interventions designed to hasten the weaning process are sorely needed. This 
is particularly true for patients requiring long-term MV due to their significant 
healthcare costs and increased risk of morbidity and mortality.4–6. 
4 VentFree  
VentFree (Liberate Medical, LLC) is a neuromuscular electrical stimulation (NMES) 
device that applies transcutaneous electrical stimulation to the abdominal wall 
muscles (primarily rectus abdominis and external oblique) in synchrony with a 
patient’s voluntary exhalation.  
Figure 1 Illustration of the imbalance between an excessive respiratory load and 
reduced respiratory muscle strength 

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NMES elicits muscle contractions through the delivery of small electrical pulses to 
motor nerves that supply a given muscle.16 When NMES is applied to the abdominal 
wall muscles in synchrony with exhalation, the effect on ventilation is similar to a 
physiological contraction of the muscles.17 An important advantage of VentFree, 
however, is that it can be used to recruit the abdominal wall muscles in the absence 
of patients’ voluntary or automatic recruitment of these muscles (i.e. severe atrophy 
or paralysis). Accordingly, the VentFree technology provides a convenient and 
consistent method of producing contractions of the abdominal wall muscles for 
training/strengthening purposes. 
4.1 Study Device 
This study will use the VentFree prototype (model number: VF03-K) that consists of 
a commercially available and FDA cleared neuro muscular electrical stimulator 
(Continuum, Empi, USA) and a stimulation trigger (designed by Liberate Medical). 
The disposable components of the device are single patient use and include two sets 
of 4 cm by 5 cm rectangular stimulation electrodes (PALS Platinum) and a variable 
orifice pneumotachograph (Braebon). A picture of the device is shown in Error! 
Reference source not found..  
 
The main features of the device are: 
x Exhalation synchronized stimulation to the abdominal wall muscles – 
the device allows the timing and duration of the stimulation burst as well as 
the parameters of the stimulation pulses to be modified by the user.  
Figure 2 VentFree picture 

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x Expiratory flow limitation test – this mode of the device records the output 
of the respiratory sensor for the purposes of conducting an expiratory flow 
limitation test (see Section 11.8).  
x Compliance monitoring – the time, date and the duration of each 
stimulation session is recorded by the device.  
4.2 Overview of Clinical Studies  
A detailed description of the clinical effects of VentFree is included in the 
Investigators Brochure.  This includes the results from: (1) a structured literature 
review that evaluated the safety and performance of the effect of abdominal muscle 
stimulation on respiratory function; (2) four prospective clinical trials of VentFree, 
which collectively included a total of 52 subjects; and (3) a structured review of 
muscle stimulation adverse events reported to the Food and Drug Administration, 
Manufacturer and User Facility Device Experience (MAUDE) database. The main 
findings from this work includes: 
1. AFES in synchrony with exhalation can be used to both acutely improve 
respiratory function, whereby the user’s respiratory function is temporarily 
improved when they are using the device, and to chronically improve 
respiratory function, whereby a training intervention of the device results in 
an improvement in the patient’s unassisted respiratory function.  
2. Fourteen articles, two Ph.D. theses and all four of Liberate Medical’s 
prospective clinical trials supported the acute effects of AFES. This research 
showed that during AFES-assisted, compared with unassisted, resting 
breathing tidal volume and minute ventilation were augmented in healthy 
subjects, patients with COPD, and patients receiving prolonged MV. In 
addition, Liberate Medical’s trials demonstrated that the AFES-induced 
augmentation in minute ventilation during resting breathing was associated 
with a reduction in the inspiratory work of breathing. Lastly, studies in the 
literature demonstrated that AFES could be used to augment cough peak 
flow in patients with spinal cord injury.  
3. Six articles and two Ph.D. theses investigated the chronic (training) effect of 
AFES. The majority of these studies included patients with spinal cord injury 
and they all found that FVC, FEV1 and PEF increased in response to AFES 
training. Three studies included a follow up period, which ranged from 3 
months to 6 months. While these studies indicated that the improvement in 
respiratory function was maintained after training ceased, the long-term 
effect of AFES remains to be established.  
A small number of adverse events were reported in the literature. These were 
minor, infrequent and transient in nature. No adverse events have been reported in 
Liberate Medical clinical studies conducted to date. The FDA MAUDE database 
included reports of injuries and malfunctions resulting from electrical stimulation 
devices. The reported adverse events were minor in nature, and no further 
complications were reported. Based on the available safety information, AFES offers 
an acceptable safety profile. 
 

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The combined results from the prospective clinical trials conducted by Liberate 
Medical and the literature included in the structured literature review have 
demonstrated that abdominal stimulation applied in synchrony with exhalation can 
be used to acutely improve breathing volumes in a range of different patient groups. 
In addition the studies cited in the literature review indicate that abdominal muscle 
training using electrical stimulation can be used to improve unassisted respiratory 
function in SCI and that this improvement is sustained after the cessation of 
stimulation training. Finally, two studies indicate that abdominal stimulation may be 
able to be used to assist ventilator weaning. However, additional studies are 
required to verify the abdominal muscle training results in additional patient groups 
and to determine the functional benefit of abdominal stimulation for patients.  
5 Objectives of the Clinical Investigation 
The primary objective of this study is to determine whether NMES applied to the 
abdominal wall muscles in synchrony with exhalation can increase the strength of 
the respiratory muscles in prolonged mechanical ventilation patients. If feasible it 
will be used to design a follow up trial on clinically relevant endpoints.  
 
The secondary objectives of the study is to evaluate whether this intervention also 
affects: (1) the thickness of the abdominal wall muscles and the diaphragm, (2) 
functional respiratory measurements, and (3) weaning outcome.  
6 Study Design 
This is a single center, participant blinded randomized placebo-controlled pilot trial 
that includes 12 patients in the intervention arm and 12 patients in the placebo arm.  
 
Screening data will be reviewed to determine participant eligibility. Patients who 
meet all of the inclusion criteria and none of the exclusion criteria and who are 
willing to participate in the study will be entered into the investigation.  
 
Each participant will receive either active or placebo electrical muscle stimulation to 
the abdominal wall during exhalation for sixty minutes per day, five days per week 
for the shorter of six weeks or until the patient is weaned from mechanical 
ventilation.  Participants will be assigned to active or placebo stimulation in random 
order (using a random number generator). Evaluations will be performed at 
baseline, after three weeks of treatment and at the end of treatment. A flow diagram 
of the study protocol is shown in Figure 3. 
 

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Figure 3 Study Flow Diagram 
 
The maximum duration of participant participation is 45 days. The total duration of 
the study is expected to be 6 months.  
7 Outcome Measures 
7.1 Primary Outcome Measures  
The primary outcome measure in this study is:  
x Maximum Expiratory and Inspiratory Pressure – The strength of the 
inspiratory and expiratory muscles will be assessed using the maximum 
inspiratory pressure and maximum expiratory pressure test respectively.  
7.2 Secondary Outcome Measures 
The secondary outcome measures in this study are: 

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x Thickness of the Abdominal Wall Muscles – The end inspiratory and end 
expiratory thickness of the external oblique, internal oblique and transversus 
abdominis muscles will be measured using ultrasound. 
x Thickness of the Diaphragm  - The end inspiratory and end expiratory 
thickness of the diaphragm will be measured using ultrasound.  
x Weaning Success – Defined as 72 hours of spontaneous respiration without 
any mechanical ventilation support.  
x Number of Days Taken to Wean – Defined as the time from the patient’s 
original admission to the point of weaning success.  
x Time spent breathing without mechanical ventilation support - The time 
spent breathing without MV support will be recorded on a daily basis 
throughout the study. 
x Cough Peak Flow – The peak flow during a voluntary cough will be 
recorded. 
x Resting Breathing – This outcome will be assessed using measurements of 
tidal volume, respiratory rate and minute ventilation during a one-minute 
period of resting breathing. 
x Adherence to the Weaning Protocol – The number and duration of the 
weaning sessions supported by electrical stimulation during the study period 
will be recorded for each participant.  
x Sensation of Stimulation Experienced by the Patient – Surface electrical 
muscle stimulation stimulates sensory nerves in addition to motor nerves 
and can cause pain at high intensities. The degree of discomfort experienced 
by participants during stimulation will be quantified using the behavioral 
pain scale.18  
x Adverse Events – All medical complications experienced by the study 
participants during the study will be assessed for severity and relationship to 
the study device and recorded.  
8 Participant Selection 
8.1 Participant Population 
Participants who meet the inclusion and exclusion criteria will be eligible for 
participation in this study.   
8.2 Inclusion Criteria 
x Patients who have been mechanically ventilated for more than fourteen days. 
x Clinically stable: oxygen saturation > 90% with a fractional inspired oxygen ≤ 
0.40, external PEEP ≤ 5 cm H2O, temperature ranging from 35.5 to 38.5Co, no 
intravenous administration of vasoactive agents.  
8.3 Exclusion Criteria 
x Patients in whom NMES does not elicit a palpable contraction of the 
abdominal muscles.  
x Participants with broken or irritated skin on the abdominal wall. 

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x History of neuromuscular disease 
x Body mass index > 35 kg/m2 
x Patients who are note medically stable 
x Participants with a pacemaker 
x Female participants who are pregnant  
x Patients under the age of 18 
x Patients who are expected to die within four weeks 
x Patients who are unable to follow verbal instructions 
x Patients with epilepsy  
x Patients with an abdominal wall hernia  
x Patients with anoxic encephalopathy 
x Patients with history of, or active, substance abuse 
8.4 Patient Recruitment  
The research team, including research nurses, principle investigator, and the 
associate investigators will be responsible for recruitment. Eligible participants will 
be informed of their eligibility by their clinician. Patients who are interested in 
taking part will be provided with an information sheet (attached) and advised to 
discuss the study in further detail with the investigators after taking adequate time 
to digest the information in the information sheet. Written informed consent will 
then be obtained from each participant before they take part in the study. However, 
because MV is a requirement for eligibility, participants will frequently be incapable 
of informed consent at the time of inclusion. In such cases, we will obtain informed 
consent from a legally authorized representative making decisions for eligible 
patients. As the participants recover, they will be evaluated for the capacity by their 
clinician and when they are deemed to have regained capacity they will be asked to 
provide informed consent to continue in the study. 
 
Participation is entirely voluntary, with participation in no way affecting the care 
received. Patients will not be financially compensated in any way for participating in 
this study. 
9 Study Treatments 
9.1 Method of Assigning Participants to Treatment Groups 
Up to 26 eligible patients will be randomly assigned to either active or placebo 
stimulation treatment groups in a 1:1 ratio using a computer generated random 
sequence.  
9.2 Blinding   
The difference between active and placebo stimulation can be distinguished visually 
as active stimulation causes a tetanic muscle contraction whereas placebo 
stimulation causes a sub-tetanic muscle contraction. Therefore study personnel who 
apply the treatment to subject will not be blinded to study patients’ treatment group 
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The following procedures will be used to ensure that patients are blinded to the 
treatment group that they have been assigned to: 
x Study personnel will be instructed not to inform patients as to whether a 
tetanic or twitch contraction is the active or placebo treatment arm of the 
study.  
x The appearance of the active and placebo stimulation devices will be 
identical. 
 
In addition, all clinical staff not involved in the study and all study personnel who do 
not apply stimulation to patients will be blinded to the treatment group assignment 
of participants. This measure will help ensure that decisions to attempt weaning are 
unrelated to the study and are only based on clinical care. 
9.3 Active and Placebo Study Devices 
The VentFree prototype (model: VF03-K) will be used for both the active and 
placebo devices. The active stimulation device’s stimulation parameters will be set 
to cause a tetanic contraction of the abdominal muscles, whereas the placebo 
stimulation device’s stimulation parameters will be set to cause a twitch contraction 
of the abdominal muscles. All other device parameters will be identical between the 
two types of devices. The relevant stimulation parameters will be locked on each 
device so that it is not possible to accidentally change the parameters that 
distinguish the active devices from the placebo devices. 
9.3.1 Active Stimulation Device  
The active devices will use the stimulation parameters that were used during 
Liberate’s previous prospective clinical trials. Specifically: 
x Stimulation frequency = 30 Hz 
x Stimulation pulse width = 350 µs 
x Stimulation current = 90 % of the participants tolerated maximum (see 
Administration Instructions, Section 9.6).  
x Stimulation delay = 0.1 seconds after the start of exhalation. 
x Stimulation ratio – The stimulation ratio, which determines the duration of 
stimulation during exhalation as a fraction of the duration of the proceeding 
inhalation, will initially be set to 0.8. If the study researcher observes that 
stimulation does not last for the duration of exhalation, then he or she will 
increase the stimulation ratio. Similarly, if the study researcher believes that 
the duration of stimulation is too short then he or she will reduce the 
stimulation ratio.  
9.3.2 Placebo Stimulation Device   
The placebo devices will use a stimulation frequency of 10 Hz, a stimulation pulse 
width of 100 µs and a stimulation current of 10mA. The stimulation ratio will be set 
to 0.8 for all subjects. All other parameters will be set according to the active 
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9.4 Number of Study Devices 
Four stimulation timing controllers (manufactured by Liberate Medical, LLC) will be 
used for the study. Two devices will be used for the active stimulation group and 
two devices will be used for the placebo stimulation group. This will allow one 
operational device and one back up device per treatment group 
 
Four Empi Continuum stimulators will be used for the study. Two devices will be set 
to deliver active stimulation and two devices will be set to deliver placebo 
stimulation. This will allow one operational device and one back up device per 
treatment group. The Empi Continuum is an FDA cleared stimulator for multiple 
patient use.  
 
Six sets of electrodes will be provided per participant enrolled in the study to enable 
a new set of electrodes to be used every week that a patient is enrolled in the study. 
The PALS Platinum electrodes are FDA cleared electrodes that can be used multiple 
times with a single patient. 132 sets of electrodes will be used in total. 
 
One variable orifice pneumotachograph will be provided per patient enrolled in the 
study (26 provided in total). The Braebon variable orifice pneumotachographs are 
FDA cleared and can be used multiple times with a single patient.  
9.5 Packaging and Labeling of the Study Devices 
Placebo and active stimulators will be able to be distinguished using a colored 
sticker, placed on the bottom of the device, with the meaning of each color 
identifiable only to the research team. 
9.6 Device Administration  
In both of the study arms (active and placebo stimulation), stimulation will be 
administered for thirty minutes, twice per day, 5 days per week for the shorter of six 
weeks or until the patient is weaned from mechanical ventilation by one of the two 
trained study researchers.  
9.6.1 Electrode Placement 
Adhesive surface electrodes (Pals Platinum, Axelgard, CA) will be placed bilaterally 
over the posterolateral aspect of the abdominal wall as described by Lim et al.19   
Specifically, one pair of electrodes will be placed from the midline, angled diagonally 
downward, 2 cm below and parallel to the costal margin, toward the anterior 
superior iliac spine on each side of the abdomen19. A second pair of electrodes 
(cathodes) will directed from the midaxillary line at the eight thoracic vertebral 
body level obliquely down toward the posterior superior iliac spine. 19 (The 
electrodes will be positioned symmetrically on both sides of the abdomen.) 19  
9.6.2 Device Setup 
Complete instructions for use will be provided with each study device. In addition, 
each study researcher will be fully trained by the PI prior to the start of the study. 
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1. Place the electrodes on the participant’s abdomen (described in Section 
9.6.1.) 
2. Connect the electrodes to the stimulator. 
3. Connect the variable orifice pneumotachograph to the patient’s endotracheal 
tube.  
4. Connect the pneumotachograph’s pressure hoses to the stimulation timing 
controller. 
5. Turn on the stimulation timing controller and verify that the timing settings 
are correct.  
9.6.3 Stimulation Session 
At the start of the session the study researcher will apply 0.5 second bursts of 
stimulation starting from stimulation current of 5 mA and progressing in 
increments of 5 mA for each side of the abdomen until the participant reports that 
the sensation of stimulation is painful or until a maximum amplitude of 60 mA is 
reached. This upper limit in stimulation amplitude was based on the maximum 
tolerated stimulation amplitude found in our preliminary studies. A behavioral pain 
scale > 4 will be used to determine painful stimulation in patients who are unable to 
verbally communicate.18  The researcher will set the stimulation current to 90% of 
this maximum tolerable level (deemed acceptable in previous clinical studies 
performed by Liberate) and begin the session by turning on the exhalation 
synchronized stimulation mode of VentFree.  
 
Throughout the session, heart rate, blood pressure, oxygen saturation and skin 
irritation will continuously be monitored. Every ten minutes, participants will be 
asked whether the intensity of abdominal wall muscle stimulation can be increased 
or should be decreased. During these 10-minute intervals, the investigator will 
quantify pain using the behavioral pain scale. If signs of distress develop, the 
investigator will stop the session and the attending physicians will provide 
immediate medical treatment, as appropriate. Criteria for distress include: a mean 
arterial blood pressure < 60 mmHg or > 110 mm Hg, heart rate < 40 beats per 
minute or > 130 beats per minute; respiratory rate > 40 breaths per minute, SpO2 < 
90%, score of > 4 on behavioral pain scale18, agitation or patient request to stop.  
9.7 Device Deficiency/Failure 
A log will be kept by the research team of any device deficiencies or failures. Such 
events will be discussed with the sponsor and, where appropriate, a defective device 
will be repaired and or replaced. 
10 Apparatus  
The specific apparatus that will be used for the study is described below.  
10.1 Mouth Pressure Meter  
MIP and MEP will be assessed using a hand-held respiratory pressure meter 
(MicroRPM, CareFusion, USA or similar). A disposable antimicrobial air filter will be 
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10.2 Peak Expiratory Flow Meter 
PEF will be assessed using a hand-held mechanical peak flow meter. Each patient 
will be assigned an individual meter. The meter will be disinfected between uses. 
11 Study Procedures 
11.1 Concomitant Medications 
Dose, route, unit frequency of administration, and indication for administration and 
dates of medication will be captured during the Baseline Visit, Intermediate Visit 
and Final Visit. No medications will be restricted as part of this study. 
11.2 Demographics  
Demographic information (date of birth, gender, race) will be recorded during the 
Baseline Visit. 
11.3 Medical History  
Relevant medical history, including history of current disease, other pertinent 
respiratory history, and information regarding underlying diseases will be recorded 
during the Baseline Visit. 
11.4 Physical Examination 
A complete physical examination will be performed at the Baseline Visit.  
11.5 Vital Signs 
Body temperature, blood pressure, pulse and respiratory rate will be recorded after 
resting for 5 minutes at the Baseline Visit, Intermediate Visit, and Final Visit. 
11.6 Oximetry 
Oximetry will be measured on fraction of inspired oxygen set by the treating 
physician with the participant at rest at the Baseline Visit, Intermediate Visit, and 
Final Visit.   
11.7 Acute Physiology and Chronic Health Evaluation 
The Acute Physiology and Chronic Health Evaluation II (APACHE II) score will be 
calculated by a study investigator at the Baseline Visit. 
11.8 Expiratory Flow Limitation 
The presence of expiratory flow limitation will be evaluated at the Baseline Visit 
using manual compression of the abdominal wall as described by Ninane et al. 20   
During this maneuver, subjects will be asked to breathe through the VentFree 
pneumotachograph while the device is in expiratory flow limitation mode. The gentle 
manual compressions of the abdomen tests will be performed when subjects show 
regular breathing. For this purpose, the investigator will put one hand gently on the 
abdominal wall of the subject with the palm on the umbilicus oriented perpendicular to 
the axis between the xiphoid process and the pubis. Gentle palpation of the abdomen 
during two or three breathing cycles will easily allow recognition of the expiratory 
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on the abdominal wall. The gentle compression will be maintained throughout 
expiration and afterwards the investigator will remove his/her hand. If expiratory flow 
limitation is present, the gentle manual compressions of the abdomen will not increase 
expiratory flow either during the whole tidal exhalation or during part of it. On the 
other hand, if expiratory flow is absent, the gentle manual compressions of the 
abdomen will increase expiratory flow during exhalation. Gentle manual compressions 
of the abdomen are known to be well tolerated without untoward effects.  
11.9 Maximum Expiratory Pressure and Maximum Inspiratory Pressure  
Maximum Expiratory Pressure (MEP) and Maximum Inspiratory Pressure (MIP) will 
be measured at the Baseline Visit, Intermediate Visit, and Final Visit using a cuff 
inflated cannula as described by Vitacca et al. 21 
11.10 Thickness of the Abdominal Wall Muscles  
The end inspiratory and the end expiratory thickness of the external oblique, 
internal oblique and transversus abdominis muscles will be measured using 
ultrasound22 at the Baseline Visit, Intermediate Visit and Final Visit.  
11.11 Thickness of the Diaphragm  
The end inspiratory and the end expiratory thickness of the diaphragm will be 
measured using ultrasound22 at the Baseline Visit, Intermediate Visit and Final Visit.  
11.12 Cough Peak Flow 
CPF will be measured at the Baseline Visit, Intermediate Visit, and Final Visit 
through a deflated cuff as described by Winck et al.23 
11.13 Sensation of Stimulation  
The participant’s sensation of stimulation will be measured using the behavioral 
pain scale every five minutes while receiving electrical muscle stimulation.  
11.14 Adverse Events 
Information regarding occurrence of adverse events will be captured throughout 
the study. Duration (start and stop dates and times), severity/grade, outcome, 
treatment and relation to study device will be recorded on the case report form 
(CRF). 
11.15 Measures of Treatment Compliance 
The study treatment devices will automatically record the date, time and duration of 
stimulation for an individual patient to a memory card.   
12 Study Schedule 
A Schedule of Events representing the required testing procedures to be performed 
for the duration of the study is diagrammed in Appendix 1. A description of each 
procedure is provided in Section 11. 
 

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Prior to conducting any study-related activities, written informed consent and the 
Health Insurance Portability and Accountability Act (HIPAA) authorization must be 
signed and dated by the participant.   
12.1 Baseline Visit - Day 1 
On day 1 the investigators will review the study with the participant and obtain 
written informed consent and HIPAA authorization. After consent has been obtained 
they will record the patient’s demographic data, medical history and concomitant 
medications.  
 
The investigators will determine if the patient meets the study inclusion and 
exclusion criteria. If the patient does not meet the criteria then no further 
procedures will be performed and they will be withdrawn from the study. If the 
patient does meet the criteria then the investigator will randomize the patient to a 
treatment group. 
 
The study researcher will record their vital signs, oximetry, expiratory flow 
limitation, APACHE II score, MIP, MEP, thickness of the abdominal wall muscles and 
diaphragm, CPF and resting breathing parameters.  
12.2 Stimulation Visits – Days 2 - 22 
Patients will participate in Stimulation Visits two 2 per day in 5 days every week. 
Specifically, patients will participate in morning and afternoon Stimulation Visits 5 
times between days 2 and 8, 5 times between days 9 and 15 and 5 times between 
days 15 and 22.  
 
The investigators will administer sixty minutes of stimulation to the participant as 
described in Section 9.6. In addition, the investigators will record adverse events 
related to stimulation or otherwise.  
12.3 Intermediate Visit – Day 23 
The Intermediate Visit will ideally take place on day 21. However, if necessary the 
Intermediate Visit may be conducted no earlier than day 20 and no later than day 
25, providing that it occurs after 15 Stimulation Visits. 
 
At the start of the visit the investigators will measure MEP, MIP, CPF, thickness of 
the abdominal wall muscles and diaphragm, resting breathing parameters, changes 
to medications and adverse events related to stimulation or otherwise.  
12.4 Stimulation Visits – Days 24 – 44 
Patients will participate in a Stimulation Visits 2 times per day in 5 days every week. 
Specifically, patients will participate in morning and afternoon Stimulation Visits 5 
times between days 24 and 30, 5 times between days 31 and 37 and 5 times 
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The stimulation session will then continue as described in Section 9.6. In addition, 
the investigators will record adverse events related to stimulation or otherwise.  
12.5 Final Visit – Day 45 
The Final Visit will ideally take place on day 45. However, if necessary the Final Visit 
may be moved no earlier than day 43, providing that it occurs 15 Stimulation Visits 
after the Intermediate Visit, and no later than day 47. 
 
During this visit the investigators will record the participant’s MEP, MIP, thickness 
of the abdominal wall muscles and diaphragm, CPF, resting breathing parameters 
and adverse events related to stimulation or otherwise. 
12.6 Early Withdrawal Visit 
In the case that the patient withdraws or is withdrawn from the protocol (see 
Section 14) before the end of the intervention period, and providing the patient 
consents, then the investigators will perform and record the participant’s MEP, MIP, 
thickness of the abdominal wall muscles and diaphragm, CPF, resting breathing 
parameters and adverse events related to stimulation or otherwise. 
 
If the participant is withdrawn from the study because they have successfully 
weaned from mechanical ventilation then the study researcher will also calculate 
and record the number of days taken to wean taken from the institution of 
mechanical ventilation. 
13 Adverse Experience Reporting and Documentation 
13.1 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a clinical 
investigation of a patient administered an investigational product and that does not 
necessarily have a causal relationship with the treatment.  An AE is therefore any 
unfavorable and unintended sign (including an abnormal laboratory finding), 
symptom or disease temporally associated with the administration of an 
investigational product, whether or not related to that investigational product.  An 
unexpected AE is one of a type not identified in nature, severity, or frequency in the 
current Investigator’s Brochure (attached) or of greater severity or frequency than 
expected based on the information in the Investigator’s Brochure. 
 
The Investigator will probe, via discussion with the participant, for the occurrence 
of AEs during each participant visit and record the information in the site’s source 
documents.  AEs will be recorded in the patient CRF.  AEs will be described by 
duration (start and stop dates and times), severity, outcome, treatment and relation 
to study device or if unrelated, the cause. 
AE Severity 
The National Cancer Institute’s Common Terminology Criteria for AEs (CTCAE) 
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abnormalities judged to be clinically significant. The guidelines shown in Table 1 
below should be used to grade severity.  It should be pointed out that the term 
“severe” is a measure of intensity and that a severe AE is not necessarily serious. 
Table 1  AE Severity Grading 
Severity (Toxicity Grade) 
Description 
Mild (1) 
Transient or mild discomfort; no limitation in activity; no 
medical intervention or therapy required. The participant 
may be aware of the sign or symptom but tolerates it 
reasonably well. 
Moderate (2) 
Mild to moderate limitation in activity, no or minimal 
medical intervention/therapy required. 
Severe (3) 
Marked limitation in activity, medical intervention/therapy 
required, hospitalizations possible. 
Life-threatening (4) 
The participant is at risk of death due to the adverse 
experience as it occurred. This does not refer to an 
experience that hypothetically might have caused death if 
it were more severe. 
 
AE Relationship to Study Device 
The relationship of an AE to the study device should be assessed using the following 
the guidelines in Table 2. 
Table 2  AE Relationship to Study Device 
Relationship 
to Device 
Comment 
Definitely 
Previously known adverse event; or an event that follows a reasonable 
temporal sequence from administration of the device; that follows a 
known or expected response pattern to the suspected device; that is 
confirmed by stopping administration of the device; and that is not 
explained by any other reasonable hypothesis. 
Probably 
An event that follows a reasonable temporal sequence from 
administration of the device; that follows a known or expected 
response pattern to the suspected device; that is confirmed by stopping 
the administration of the device; and that is unlikely to be explained by 
the known characteristics of the participant’s clinical state or by other 
interventions. 
Possibly 
An event that follows a reasonable temporal sequence from 
administration of the device; that follows a known or expected 
response pattern to that suspected device; but that could readily have 
been produced by a number of other factors. 
Unrelated 
An event that can be determined with certainty to have no relationship 
to the study device. 
13.2 Serious Adverse Experiences (SAE) 
An SAE is defined as any AE occurring at any dose that results in any of the following 
outcomes: 
x death 
x a life-threatening adverse experience 
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x a persistent or significant disability/incapacity 
x a congenital anomaly/birth defect  
Other important medical events may also be considered an SAE when, based on 
appropriate medical judgment, they jeopardize the participant or require 
intervention to prevent one of the outcomes listed.  
13.2.1 Serious Adverse Experience Reporting 
Study sites will document all SAEs that occur (whether or not related to study 
device).  The collection period for all SAEs will begin after informed consent is 
obtained and end after procedures for the final study visit have been completed. 
In accordance with the standard operating procedures and policies of the local 
Institutional Review Board (IRB)/Independent Ethics Committee (IEC), the site 
investigator will report SAEs to the IRB/IEC.   
13.3 Medical Monitoring 
Dr Franco Laghi should be contacted directly at these numbers to report medical 
concerns or questions regarding safety. 
Phone: (708) 528-1807 
Pager: (708) 216-8777 x :13312 
14  Discontinuation And Replacement of participants 
14.1 Withdrawal of Participants from the Study 
A participant may be withdrawn from study treatment at any time if the participant, 
the investigator, or the Sponsor feels that it is not in the participant’s best interest to 
continue.  The following is a list of possible reasons for study treatment 
discontinuation:  
x 
Successful weaning from mechanical ventilation 
x 
Participant withdrawal of consent  
x 
Participant is not compliant with study procedures 
x 
Adverse event that in the opinion of the investigator would be in the best 
interest of the participant to discontinue study treatment 
x 
Protocol violation requiring discontinuation of study treatment 
x 
Lost to follow-up 
x 
Sponsor request for early termination of study 
x 
Positive pregnancy test (females) 
If a participant is withdrawn from treatment due to an adverse event, the participant 
will be followed and treated by the PI until the abnormal parameter or symptom has 
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All participants who discontinue study treatment should come in for an early 
discontinuation visit as soon as possible. 
All participants are free to withdraw from participation at any time, for any reason, 
specified or unspecified, and without prejudice. This will not affect the care they 
receive, now or in the future. 
Reasonable attempts will be made by the investigator to provide a reason for 
participant withdrawals.  The reason for the participant’s withdrawal from the study 
will be specified in the participant’s source documents. 
12.3 Replacement of Participants 
While it is estimated that 24 is a suitable sample size for this study, the actual study 
sample size of 26 allows for a 10% drop out rate. Therefore, up to two participants 
who withdraw from the study will be replaced. 
15 Protocol Violations 
A protocol violation occurs when the participant, investigator, or Sponsor fails to 
adhere to significant protocol requirements affecting the inclusion, exclusion, 
participant safety and primary endpoint criteria.   
Failure to comply with Good Clinical Practice (GCP) guidelines will also result in a 
protocol violation. The Sponsor will determine if a protocol violation will result in 
withdrawal of a participant. 
When a protocol violation occurs, it will be discussed with the investigator and a 
Protocol Violation Form detailing the violation will be generated. This form will be 
signed by a Sponsor representative and the Investigator. A copy of the form will be 
filed in the site’s regulatory binder and in the Sponsor’s files. 
16 Protocol Amendments 
Amendments to the clinical investigation plan must be submitted to the Sponsor for 
review before submitting to the appropriate IRB for approval.  
17 Statistical Methods and Considerations 
Only participants who fulfil the protocol in terms of eligibility, interventions and 
outcome assessment will be included in the statistical analysis. Patient variables will 
be presented using means and standard deviations for continuous normally 
distributed variables, medians and interquartile ranges for continuous non-
normally distributed variables, and proportions and absolute numbers for 
categorical variables. 
 
Adverse event rates will be coded by body system and MedDra classification 
term.  Adverse events will be tabulated by treatment group and will include the 
number of patients for whom the event occurred, the rate of occurrence, and the 
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Study results will first undergo descriptive level statistical analyses.  For continuous 
variables, Two-way, Student’s t-tests will then be carried out using unequal 
variances where the variables are normally distributed.  Tests for normality will be 
carried out using the Shapiro-Wilk method.  Variables that are not normal in 
distribution that also cannot be log transformed to a normal distribution curve will 
be analysed using the Mann-Whitney U test or other non-parametric methods to be 
determined based on actual data distributions. 
 
In the second level of analysis, we will quantify the magnitude to which abdominal 
NMES exhibits a protective effect.  Crude and adjusted linear regression models will 
be carried out where the outcome variable is continuous and the covariates are 
normally distributed or categorical. Our prior experience with measures of 
respiratory function, which will be measured in this study, indicate that select 
covariates may need to be controlled for or otherwise do not always fit a normal 
distribution.  Therefore, crude and adjusted generalized linear models are 
anticipated.  These regression models will be carried out at the point of successful 
wean. All multiple regression covariates, linear or generalized, will be assessed for 
interaction, collinearity and confounding.  For all unadjusted and adjusted 
multinomial models the overall model log likelihood ratio and Hosmer and 
Lameshow goodness-of-fit will be conducted to ensure models report significance 
and are not over fitted.  Adjusted regression models will undergo sensitivity analysis 
and bootstrap analyses.  Bootstrap analysis is a re-sampling strategy to estimate the 
population parameter of interest based on the observed, sample data. 
 
The number of tries to successful wean will be quantified using Poisson regression.  
Crude and adjusted models will be carried out. Kaplan-Meier survival analysis will 
be carried out to quantify differences in the time to wean in the treatment 
abdominal NMES modality compared to the control.  As the patients will be resident 
in hospital facilities, we do not anticipate significant methodological concerns with 
respect to censoring. 
17.1 Sample Size  
This study is intended to be a pilot study that will be used to obtain initial data on 
the feasibility and safety of VentFree to assist in the process of ventilator weaning. 
The primary outcome of this study is the effect of abdominal NMES on respiratory  
muscle strength over time. There is currently no data in the literature to support a 
sample size calculation for this study. Given this constraint, in this pilot study a total 
of 24 participants was deemed adequate and is consistent with sample size 
recommendations in the literature.1 Allowing for a 10% drop out rate, up to 26 
participants will be recruited for this study. The data collected on the secondary 
endpoints will be used to determine the participants needed for a future 
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18 Data Collection, Retention and Monitoring 
18.1 Data Collection Instruments 
The PI and his research associates will prepare and maintain adequate and accurate 
source documents designed to record all observations and other pertinent data for 
each participant treated with the study treatment.   
 
Study personnel at each site will enter data from source documents corresponding 
to a participant’s visit into the protocol-specific paper case report form (CRF) when 
the information corresponding to that visit is available.  Participants will not be 
identified by name on any study documents to be collected by the Sponsor (or 
designee), but will be identified by a participant number and initials. 
 
If a correction is made on a CRF, the study staff member will line through the 
incorrect data, write in the correct data and initial and date the change. 
 
The PI and his research associates are responsible for all information collected on 
participants enrolled in this study.  All data collected during the course of this study 
must be reviewed and verified for completeness and accuracy by the Investigator.  A 
copy of the CRF will remain at the Investigator’s site at the completion of the study. 
18.2 Availability and Retention of Investigational Records 
The Investigator must make study data accessible to the monitor, other authorized 
representatives of the Sponsor (or designee), IRB/IEC, and Regulatory Agency (e.g., 
FDA) inspectors upon request.  A file for each participant must be maintained that 
includes the signed Informed Consent, HIPAA Authorization and copies of all source 
documentation related to that participant.  The Investigator must ensure the 
reliability and availability of source documents from which the information on the 
CRF was derived. 
All study documents (patient files, signed informed consent forms, copies of CRFs, 
Study File Notebook, etc.) must be kept secured for a period of two years following 
the completion of the study.  There may be other circumstances for which the 
Sponsor is required to maintain study records and, therefore, the Sponsor should be 
contacted prior to removing study records for any reason. 
18.3 Monitoring 
Monitoring visits will be conducted by representatives of the Sponsor according to 
the U.S. CFR Title 21 Parts 50, 56, and 312 and ICH Guidelines for GCP (E6). By 
signing this protocol, the Investigator grants permission to the Sponsor (or 
designee), and appropriate regulatory authorities to conduct on-site monitoring 
and/or auditing of all appropriate study documentation. 
18.4 Participant Confidentiality 
Research personnel will have access to all study records, which may include patient 
identifiable information. In order to maintain participant confidentiality, only a 

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participant number and participant initials will identify all study participants on 
CRFs and other documentation submitted to the Sponsor.   
 
Physical copies of study records will be kept in a locked office. Electronic versions of 
study records will be kept on a password protected computer.  
 
Data collected during this study will not be used for any other purpose than that for 
which the subjects consented.  
 
Additional participant confidentiality issues (if applicable) are covered in the 
Clinical Study Agreement. 
19 Statement of Compliance 
This study will be conducted according to the principles of the Declaration of 
Helsinki (version October 2013) and in accordance with the ICH Guidelines for GCP 
(E6) and ISO 14155:2011 clinical investigations of medical devices for human 
subjects – good clinical practice. 
20 Publication Policy 
Data obtained from the current study will be submitted for publication to an 
international peer reviewed journal. 
21 References 
1. 
Julious, S. A. Sample size of 12 per group rule of thumb for a pilot study. Pharm. Stat. 4, 287–
291 (2005). 
2. 
Mehta, A. B., Syeda, S. N., Wiener, R. S. & Walkey, A. J. Epidemiological trends in invasive 
mechanical ventilation in the United States: A population-based study. J. Crit. Care (2015). 
doi:10.1016/j.jcrc.2015.07.007 
3. 
Zilberberg, M. D., de Wit, M. & Shorr, A. F. Accuracy of previous estimates for adult prolonged 
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22 APPENDIX A: SCHEDULE OF EVENTS 
 
 
Baseline 
Day 1 
Stimulation 
Visits 
Days 2 - 22 
Intermediate 
Visit 
Day 23 
Stimulation 
Visits 
Days 24 - 44 
Final 
Visit 
Day 45 
Early 
Withdrawal 
Informed Consent  
X 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
Concomitant Medications 
X 
 
X 
 
X 
X 
Complete Physical Exam 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
Vital Signs 
X 
 
 
 
 
 
Oximetry 
X 
 
 
 
 
 
Expiratory Flow Limitation 
X 
 
 
 
 
 
APACHE II 
X 
 
 
 
 
 
Maximum Expiratory Pressure 
X 
 
X 
 
X 
X 
Maximum Inspiratory Pressure 
X 
 
X 
 
X 
X 
Abdominal Wall Thickness 
X 
 
X 
 
X 
 
Diaphragm Thickness 
X 
 
X 
 
X 
 
Cough Peak Flow 
X 
 
X 
 
X 
X 
Tidal Volume 
X 
 
X 
 
X 
X 
Respiratory Rate 
X 
 
X 
 
X 
X 
Minute Ventilation 
X 
 
X 
 
X 
X 
Administration of Stimulation   
 
X 
 
X 
 
 
Sensation of Stimulation 
 
X 
 
X 
 
 
Adverse Events 
X 
X 
X 
X 
X 
X 
Time spent breathing without 
mechanical ventilation support 
X 
X 
X 
X 
X 
X 
Number of Days Taken to Wean 
 
 
 
 
 
X 

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Version Date: 15th September 2016 
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