Response to Diaphragmatic Pacing in Subjects With Pompe Disease
Conditions: Pompe Disease
Sponsor: University of Florida

Response to Diaphragmatic Pacing in Subjects with Pompe Disease 
NCT02354651 
Document Date: 12/05/2016 
 

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1. Project Title 
Response to Diaphragmatic Pacing in Subjects with Pompe Disease 
2. Investigators: 
Barbara Smith, PT, PhD 
 
 
Sub-Investigators: 
Barry Byrne, MD, PhD 
Manuela Corti, PT, PhD 
Saleem Islam, MD 
Terry Sexton, MSN, ARNP 
Chasen Croft, MD 
Brittany Knight, MSN, ARNP, CPNP-PC 
Kara Godwin, MSN, ARNP, CPNP-PC 
 
3. Abstract: 
Diaphragm pacing is approved for replacing positive-pressure ventilators in neurodegenerative 
conditions including spinal cord injury and amyotrophic lateral sclerosis. Evidence shows that 
neurodegeneration plays a vital role to chronic ventilatory insufficiency in Pompe disease, which 
suggests that pacing may also benefit Pompe patients. This strategy has been shown to replace the 
role of mechanical ventilation during waking hours in patients with Pompe disease. The proposed 
study will evaluate the duration and pattern of spontaneous, versus paced ventilation in patients 
with Pompe disease and respiratory insufficiency. Medical records will be reviewed to document 
chemistry and hematology labs, chest x-ray, and review of symptoms for comorbidity. Functional 
outcomes include tolerance to breathing without positive pressure ventilators, and clinical and 
electrophysiological tests of respiratory muscle function. 
4.  Background: 
The NeuRx DPS (Diaphragm Pacer) is a medical device approved for use in ventilator-dependent 
patients with spinal cord injury and patients with moderate ventilatory insufficiency due to 
amyotrophic lateral sclerosis. Pacing acts by bypassing the descending corticobulbar drive through 
the phrenic motor system to directly depolarize the diaphragm [1]. Diaphragm electrodes are 
implanted laparoscopically near the motor point of each hemi-diaphragm [2,3]. An external 
generator is connected to the externalized wire electrodes and emits an electrical impulse that 
directly stimulates the diaphragm muscle. In patients with phrenic neural insufficiency and yet 
residual contractility of the diaphragm, pacing can serve as an electrical ventilatory prosthesis, 
reducing or replacing positive pressure ventilation [4]. In occasional patients, spontaneous 
recovery of motor function has been reported after pacing, which has enabled removal of the 
pacing wires to restore fully independent breathing [5].  
The preponderance of the preclinical and clinical evidence illustrates that respiratory insufficiency 
in Pompe disease is due to diminished phrenic motor function [6-9]. We evaluated an adult who 

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transferred to our center with Pompe disease and >four years of ventilator dependence. A 
multidisciplinary evaluation confirmed diaphragm paresis as the principal cause of his ventilatory 
insufficiency. In August  2011, a diaphragm pacing implantation was performed under guidelines 
of the FDA Humanitarian Device Exemption (HDE HO70003) for a Humanitarian Use Device 
(HUD 06-0165), following Institutional Review Board approval (UF-IRB-01# 399-2011). Five 
days after implantation of the device, progressive diaphragm conditioning was initiated. By post-
operative day #65, the patient was pacing continuously, breathing without the ventilator for 12 
hours per day, and was discharged home. We have since completed diaphragm pacing for infantile 
onset disease with similar functional results. In light of the early successes with diaphragm pacing, 
patient interest in the procedure has surged. However, the widespread use of this modality requires 
a further understanding of the magnitude of the clinical benefit as well as possible mechanisms 
behind the gains. 
5. Specific Aims: 
The global objective of this study is to determine the effect of diaphragm pacing on respiratory 
function in subjects with Pompe disease.  
 
Aim 1: to test the hypothesis that even a single bout of diaphragm pacing transiently 
augments diaphragm/phrenic activation and increases breathing capacity.  
The timing, flow, volume, and pressure generated during resting breathing, along with 
diaphragm EMG will be recorded throughout six months of diaphragm pacing and progressive 
diaphragm conditioning.  
   
Aim 2: to test the hypothesis that prolonged diaphragm pacing elicits prolonged 
rehabilitative effects on minute ventilation and ventilator weaning. 
Breath timing and volume in spontaneous breathing, breath strength, minute ventilation, 
ventilator weaning, diaphragm EMG, and sleep hypoventilation will be recorded throughout six 
months of diaphragm pacing and progressive diaphragm conditioning. 
6. Research Plan: 
Subjects: 
The study group will consist of twelve male or female subjects 2-65 years of age with a 
diagnosis of Pompe disease as defined by mutational analysis, GAA enzyme activity assay in 
blood spot and/or fibroblast culture less than 40% of control values, as well as clinical 
symptoms. In addition, subjects will be eligible if they have met the clinical eligibility for NeuRx 
DPS implantation.  All subjects will have a history of mechanical ventilation (MV) dependence, 
defined as a requirement of six or more hours invasive or non-invasive MV support daily for at 
least 21 days in duration [10]. Subjects currently on GAA replacement therapy will continue 
protein replacement during the study.   
 
Subjects will be recruited either via self-referral to the research team (e.g. after discovering the 
study on ClinicalTials.gov), or referral from the surgeon who conducts the implantation surgery. 
The surgeon will provide subjects with the contact information of the study team, so that they 
may inquire to us about the study. 
 

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Exclusionary Criteria:  
The subject must not: 
 Be participating in another treatment study using a device for diaphragm pacing 
 Be unable to complete pulmonary function testing 
 Be pregnant, or become pregnant throughout participation in the study. If a subject may 
be pregnant, a pregnancy test will be performed, or results of a recent test will be used to 
confirm. 
  
 
Study design: 
Subjects with Pompe disease who are having NeuRx DPS implantation will be invited to 
participate in this study. This procedure is part of the subject’s clinical care, and is not done for 
this or any other research project. Baseline data will be entered into the study record from 
clinical testing completed within 12 months of NeuRx DPS implant.  After placement of DPS, 
study assessments will be completed at Days 3, 14, 90 and 180 per table of events on page 8. 
 
Testing: 
Pulmonary function testing equipment and test administration protocols will be standardized in 
accordance with ATS/ERS guidelines [12]. Pulmonary function testing will be conducted 
according to the schedule of assessments (page 8).  During pulmonary function testing, baseline 
and exertional vital signs will be monitored (heart rate, respiratory rate, pulse oximetry). In 
addition, diaphragm EMG will be recorded, either with surface electrodes (global inspiratory 
muscle EMG) or by using an adaptor that enables direct EMG recording from the intramuscular 
pacing wires. These tests will be completed with support from any mechanical ventilation the 
subject may use. If the subject “sprints” routinely with reduced or no breathing support, we will 
also test breathing under these conditions. The following pulmonary function tests will be 
completed on all subjects: 
Forced expiratory tests: Forced expiratory tests measure the maximal airflow and volume of gas 
that can be exhaled with the subject breathing or coughing forcefully. A nose clip, or cuffed 
tracheostomy with cuff inflated is used to prevent leakage. The subject deeply inhales and then 
exhales as forcefully and deeply as possible. Measurements will be obtained with the subject 
sitting upright and then repeated with the subject in the supine position, if tolerated.  A minimum 
of three trials will be obtained in each position with <5% variability [13].  The highest value 
obtained in each position will be reported.  Forced expiratory tests will be completed at 
Screening, Baseline, Day 14, Day 90, and Day 180.  
 
Maximal Inspiratory Pressure (MIP): MIP will be measured with a manometer connected to the 
airway opening of the subject, which occludes the airway and prevents airflow.  A nose clip will 
be used to prevent leakage and the subject is instructed to suck air from the tube with as much 
force as possible.  Measurements will be obtained with the subject sitting upright. 
Transdiaphragmatic pressure (Pdi) may be calculated with esophageal and gastric manometry 
during MIP.  The measurement will be taken three times and the best value will be reported.  
MIP will be completed at Screening, Baseline, Day 14, Day 90, and Day 180. 
 
Resting Breathing Pattern: Resting ventilatory flow and timing will be recorded with a 
pneumotachograph and pressure transducer connected to the airway opening. If a patient 

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routinely uses MV throughout the day, the sensing equipment can be placed in series to the 
breathing tubes. Resting breathing will be recorded under the following conditions: (1) using the 
subject’s routine daytime ventilatory support (ventilator, BiPAP, ETC); (2) using the subject’s 
routine daytime ventilatory support plus the diaphragm pacer; (3) using no support or the lowest 
support needed to maintain baseline minute ventilation (if the subject uses reduced or no settings 
routinely); (4) using no support or the lowest support needed to maintain baseline minute 
ventilation plus the diaphragm pacer (if the subject uses reduced or no settings routinely). 
Subjects will rest for a minimum of 30 minutes between each condition, and tests may be 
scheduled over two consecutive days as needed. Resting Breathing Pattern will be completed at 
Screening, Baseline, Day 5, Day 14, Day 30, Day 90, and Day 180. During this testing, subjects 
will not be taken below their lowest tolerated ventilator settings.   
 
Respiratory Muscle Endurance Test: This test will begin after subjects rest for a minimum of one 
hour. Subjects will be tested in the seated position while breathing through a mouthpiece with 
nose clip. When a steady state breathing pattern has been reached (noted by stable tidal volumes 
for at least 30 seconds), subjects will be instructed how to maintain the breathing rate and 
volume, with the use of visual feedback on a computer.  A threshold inspiratory load equivalent 
to 35% of the maximal inspiratory pressure will be placed on the inspiratory port of the 
mouthpiece. Subjects will be instructed to maintain the established breathing pattern during 
loaded breathing. The test will end when the subject cannot open the threshold valve for 3 
consecutive breaths, or when the subject can no longer subjectively tolerate the test and must 
remove the mouthpiece. Loaded breathing typically lasts between 2-10 minutes.  Respiratory 
Muscle Endurance Testing will be completed at Screening, Baseline, Day 90, and Day 180. 
 
Magnetic stimulation: Supramaximal, cervical magnetic stimulation of the phrenic nerves will be 
conducted with the subjects in upright with the head and trunk supported. Stimulations will be 
applied from end-expiratory lung volume. At least five stimulations will be delivered at the 
maximum stimulator output. The resulting twitch transdiaphragmatic pressure (Pdi) will be 
calculated from gastric and esophageal pressures obtained by catheter-mounted transducers, and 
compared to reference values [14]. Magnetic stimulation will be tested at screening. 
 
Sleep dysfunction: Breathing during sleep will be assessed using the BioRadio, which has the 
ability to monitor oxygen saturation, electrocardiogram, and EMG while the subject is asleep. 
This will occur at Baseline and Day 90. Subjects will be given a monitor, sensors, and 
instructions for how to set up and record during one night’s sleep, which will be returned at the 
end of their participation. 
 
 
Post-operative diaphragm conditioning:  
Typically diaphragm conditioning commences after a 5-day post-operative recovery period, 
when post-operative pain and inflammation have been controlled for >24 hours. Diaphragm 
conditioning will be progressed using an ordered protocol, which consists of gradual increases 
in: 
 
(1) The external stimulator settings. The initial external stimulator settings will be set by the 
manufacturer’s representative in the surgical suite, and any upper limits or restrictions in 

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parameters (e.g. threshold for PVC’s) will be established. The stimulator settings will be 
increased as needed.  
(2) The duration of diaphragm stimulation. Starting POD#5, the pacing system will be 
activated for one, or more30-minute trials, per day (maximum 5, 30 minute trials). The 
duration of diaphragm stimulation will be systematically increased as tolerated to 
accomplish three goals, including pain- and dyspnea-free pacing, overnight pacing, and 
continuous 24-hour pacing.  
(3) Off-ventilator spontaneous breathing (SB). On POD#5, the patient will undergo an initial 
trial of unassisted breathing with the diaphragm pacer turned on.  The duration of SB 
with pacing will be increased to tolerance, using a protocol. If the patient cannot 
complete at least 30-minute bouts of paced SB, then the focus of breathing trials will be 
reduced pressure support mechanical ventilation.   
The subject will be instructed how to operate the pacemaker equipment and be provided with a 
diaphragm conditioning home exercise program. This is part of the patient’s routine clinical care. 
Diaphragm conditioning will be completed five to seven days per week by the subject, based upon 
the subject’s daily baseline level of fatigue. 
Diaphragm conditioning will routinely occur at home, yet an investigator will continue to 
monitor progress with the home program every 7 to 21 days by telephone. We will have 
experience in remote monitoring of RMST in ventilator-dependent children and adults, and 
remotely-supervised sessions enable investigators to monitor compliance, progress the 
diaphragm conditioning, and provide feedback. 
SCHEDULE OF ASSESSMENTS 
 
 
 
SCREENING
BASELINE
D5
D14
D30
D90
D180
As Needed
Extension
Consent 
X 
 
 
Resting Breathing 
Pattern 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Respiratory Muscle 
Endurance Test 
X 
X 
 
X 
X 
X 
X 
Phrenic Nerve-Magnetic 
Stimulation 
 
X 
 
X 
 
Maximal Inspiratory 
Pressure 
X 
X 
X 
 
X 
X 
X 
X 
Forced Expiratory Tests 
X 
X 
X 
 
X 
X 
X 
X 

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EMG 
 
X 
X 
X 
X 
X 
X 
X 
Medical History/Record 
and Medications review, 
AE and Prescription 
Compliance assessment 
ONGOING 
Questionnaires 
X 
X 
 
X 
X 
X 
 
Physical exam 
 
 
X 
X 
 
X 
X 
X 
X 
Sleep dysfunction 
measure 
 
X 
 
 
 
X 
 
 
 
 
 
 
Subjects will be asked to complete a daily pacemaker/ventilator diary documenting ventilator 
assistance use and pacemaker use.  The Investigator or designee will contact the subject a 
minimum of two times per month to document adverse events, changes to medications, update the 
medical history, and assess compliance with diaphragm conditioning exercise prescription.   This 
communication may be accomplished by email, telephone, or video conference calling.   
Extension phase: 
Subjects who complete this study will have the opportunity to continue in an optional extension 
phase, wherein they would be evaluated annually, or at the request of their physician. These 
evaluations can include a physical exam, EMG recording, and pulmonary function testing. This 
extension phase will last six years, and will allow evaluation of long-term changes in ventilator 
dependence. 
Data analysis: 
We will evaluate changes in average respiratory rate and volume, integrated EMG, and daily 
independent breathing time, between 0 and 6 months. Since this is an observational pilot study, 
data will be largely descriptive. However, the data are largely quantitative and continuous. Sample 
distributions and summary statistics will be calculated for each of these outcomes. Data 
transformations will be done if non-linear distributions exist, and repeated measures ANOVA (or 
non-parametric) will quantify recovery at 6 months.  
7. Possible Discomforts and Risks: 
 
Pulmonary Function Testing 
Pulmonary function testing is used routinely in clinical medicine and has no inherent 
complications.  Pulmonary function testing will be completed by the study team on Day 5, 14 
and 180 after NeuRx DPS implantation.  If possible, the study team will complete pulmonary 
function testing the day prior to NeuRx DPS implantation. 
 
Although sustained (several minutes to several hours), intensive inspiratory loading can produce 
elevations in oxygen consumption, mean arterial pressure and diminish cardiac output, brief 

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periods of loading (<30 seconds) have not been shown to cause significant changes in cardiac 
parameters (Coast et al., 1988). Nevertheless, we have designed the protocol to include strict limits 
on baseline and exertional vital signs, in order to minimize the imposed cardiorespiratory work.  
Due to the brief duration of testing and training procedures, the incidence of blood gas dysfunction 
is extremely low. Nevertheless, end-tidal CO2 and oxygen saturation will be monitored continually.  
Respiratory testing may elicit transient fatigue or shortness of breath that resolves within several 
seconds of completion.  Frequent rests are included to prevent or minimize these systems. 
 
Phrenic Nerve Function Evaluation with EMG 
Anterior magnetic stimulation of the phrenic nerves is a recommended technique for subjects, 
because it is painless and reproducible, yields supra-maximal stimulation, and does not require 
uncomfortable positioning [12].  Phrenic latency and compound muscle action potential (CMAP) will 
be determined individually for the right and left phrenic nerves [19].  The phrenic latency is the time 
between the stimulus and the responding diaphragm CMAP.  A normal phrenic latency is between 6-
8 msec in adults [20] and 4.8-8.63 msec in children [21].  The diaphragm CMAP will be recorded 
using surface or esophageal electrodes. Alternatively, the CMAP may be captured by recording from 
the implanted pacer wires. In addition to measuring CMAP, the transdiaphragmatic pressure (Pdi) 
may be calculated with esophageal and gastric manometry during bilateral, supra-maximal magnetic 
stimulation and compared to reference values obtained in healthy adults [14]. Phrenic stimulation 
testing will be conducted at baseline and at Day 180, unless clinical care dictates more frequent 
assessments are needed. 
 
EMG recording will be completed with the implanted wires on Day 0, 5, 14, 180 and PRN. 
 
Questionnaires 
Subjects will be asked to complete the Severe Respiratory Insufficiency Questionnaire at 
Screening, baseline, day 90 and day 180.  This questionnaire was developed for use in subjects 
with respiratory failure from various etiologies who utilize mechanical ventilation.  It is a self-
administered test that will require approximately 20 minutes to complete. 
8. Possible Benefits: 
There are some potential benefits to the individual subject expected in this clinical research study.  
The anticipated benefit to subjects and the Pompe community is to determine the mechanism of 
action for respiratory insufficiency and ultimately respiratory failure in Pompe disease.  Subjects 
who participate in this clinical research study will have personalized respiratory muscle 
strengthening routine prescribed with regular contact with the study team.   
 
Another potential benefit to participants is decreased ventilator dependence.  Other respiratory 
muscle exercises have shown to be effective in adults with ventilator dependence and/or 
neuromuscular disease, as well as in children without neuromuscular diseases. The primary interest 
is whether and for how long strength and functional breathing patterns can improve for subjects 
after pacer conditioning. The training regimen may provide an alternative adjuvant treatment for 
subjects with Pompe disease who require assisted ventilation. 
9. Conflict of Interest: 

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There are no declared conflicts of interest for the investigators. 

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