Pompe Disease
Conditions
Keywords
Pompe disease, mechanical ventilation, diaphragm pacing
Brief summary
The purpose of this study is to determine the effect of diaphragm pacing on respiratory function in subjects with Pompe disease by evaluating the duration and pattern of spontaneous respiratory function versus paced ventilation respiratory function in patients with Pompe disease who have received the NeuDx Diaphragm pacer (DPS).
Detailed description
Subjects with Pompe disease who are scheduled to receive a NeuRx Diaphragm pacer (DPS) will be invited to participate in this study. The following tests will be performed during participation in the study: 1. Forced expiratory tests 2. Maximal Inspiratory Pressure (MIP) 3. Resting Breathing Pattern 4. Phrenic Nerve Function Evaluation with EMG 5. Severe Respiratory Insufficiency Questionnaire 6. Magnetic stimulation 7. Diaphragm conditioning consisting of: 1. The external stimulator settings 2. The duration of diaphragm stimulation 3. Off-ventilator spontaneous breathing (SB)
Interventions
OTHERDiaphragm conditioning via phrenic nerve stimulation
Diaphragm pacing will be prescribed by the patient's clinical team.
Sponsors
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Florida
Study design
Observational model
COHORT
Time perspective
PROSPECTIVE
Eligibility
Sex/Gender
ALL
Age
2 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
* 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 value * Medically and functionally eligible for NeuRx DPS implantation, as determined by a clinical surgical evaluation. The surgeon will determine eligibility through pulmonary function tests, ability to stimulate your diaphragm, and arterial blood gas levels. Eligibility may also be determined by your response to traditional respiratory strengthening exercises without a pacemaker. * History of mechanical ventilation dependence (six or more hours of invasive or non-invasive mechanical ventilation support daily for at least 21 days in duration
Exclusion criteria
* Current participation in another treatment study (other than enzyme replacement therapy) directed at improving diaphragm function * Unable to complete pulmonary function testing
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Off-ventilator Spontaneous Breathing (SB) at Baseline and Day 180 | Baseline, Day 180 | 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 initially complete at least 30-minute bouts of paced SB, then the focus of breathing trials will be to breathe with reduced support from the mechanical ventilator. These measures were generated utilizing ventilator chip data for SB that has been averaged. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Resting Breathing Pattern | Day 180 | Resting ventilatory flow and timing will be recorded with a pneumotachograph and pressure transducer connected to the airway opening, to calculate minute ventilation. If a patient routinely uses MV throughout the day, the sensing equipment can be placed in series to the breathing tubes. Breathing pattern will be measured for a minimum of ten minutes. |
| Diaphragm Electromyogram (EMG) at Day 180 | Day 180 | This activity reflects the activity of the diaphragm and phrenic nerve. The wires that are implanted for diaphragm pacemaker will be connected to a computer and recording equipment to monitor the activity of the diaphragm muscle during breathing at the lowest level of ventilator assistance. This EMG data is measured in units of microvolts per second and expressed as a percentage of the level of diaphragm EMG activity recorded during MIP maneuvers. |
| Maximal Inspiratory Pressure (MIP) at Baseline and Day 180 | Baseline, Day 180 | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Magnetic Stimulation | 180 Days | EMG response to supramaximal bilateral stimulation of the phrenic nerves. |
| Severe Respiratory Insufficiency Questionnaire | 180 days | Patient reported measure of impact of respiratory insufficiency on functional mobility |
| Forced Expiratory Flow | 180 days | Peak expiratory flow obtained during voluntary cough |
| Hours Per Day of Diaphragm Pacing | 180 days | Number of hours used per day diaphragm pacing occurred by subjects |
Countries
United States
Participant flow
Pre-assignment details
Subjects were eligible to receive a diaphragmatic pacemaker as part of their clinical care. Some subjects who enrolled decided not to include pacing as part of their clinical care (n=2), or were found to have medical conditions that made them ineligible (n=1).
Participants by arm
| Arm | Count |
|---|---|
| Pompe Subjects Receiving NeuDx DPS Patients will receive resting breathing pattern evaluation, phrenic nerve stimulation, maximal inspiratory pressure (MIP) testing, forced expiratory testing, and EMG.
Diaphragm conditioning via phrenic nerve stimulation: Diaphragm pacing will be prescribed by the patient's clinical team. | 6 |
| Total | 6 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Physician Decision | 1 |
| Overall Study | Withdrawal by Subject | 2 |
Baseline characteristics
| Characteristic | Pompe Subjects Receiving NeuDx DPS |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants |
| Age, Continuous | 24.5 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 5 Participants |
| Sex: Female, Male Female | 3 Participants |
| Sex: Female, Male Male | 3 Participants |
| Ventilator-Free Breathing | 0.52 hours of unassisted ventilation per day |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 0 / 6 |
| other Total, other adverse events | 6 / 6 |
| serious Total, serious adverse events | 3 / 6 |
Outcome results
Primary
Off-ventilator Spontaneous Breathing (SB) at Baseline and Day 180
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 initially complete at least 30-minute bouts of paced SB, then the focus of breathing trials will be to breathe with reduced support from the mechanical ventilator. These measures were generated utilizing ventilator chip data for SB that has been averaged.
Time frame: Baseline, Day 180
Population: Full sample
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Off-ventilator Spontaneous Breathing (SB) at Baseline and Day 180 | Baseline | 0.52 hours per day |
| Pompe Subjects Receiving NeuRx DPS | Off-ventilator Spontaneous Breathing (SB) at Baseline and Day 180 | Day 180 | 4.72 hours per day |
Secondary
Change in Resting Breathing Pattern
Resting ventilatory flow and timing will be recorded with a pneumotachograph and pressure transducer connected to the airway opening, to calculate minute ventilation. If a patient routinely uses MV throughout the day, the sensing equipment can be placed in series to the breathing tubes. Breathing pattern will be measured for a minimum of ten minutes.
Time frame: Day 180
Population: Minute ventilation during off-ventilator breathing was assessed with and without diaphragm pacing at approximately 6 months post-implant.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Change in Resting Breathing Pattern | Without diaphragm pacer | 5.05 L/min | Standard Deviation 1.73 |
| Pompe Subjects Receiving NeuRx DPS | Change in Resting Breathing Pattern | With diaphragm pacer | 5.41 L/min | Standard Deviation 3.54 |
Secondary
Diaphragm Electromyogram (EMG) at Day 180
This activity reflects the activity of the diaphragm and phrenic nerve. The wires that are implanted for diaphragm pacemaker will be connected to a computer and recording equipment to monitor the activity of the diaphragm muscle during breathing at the lowest level of ventilator assistance. This EMG data is measured in units of microvolts per second and expressed as a percentage of the level of diaphragm EMG activity recorded during MIP maneuvers.
Time frame: Day 180
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Diaphragm Electromyogram (EMG) at Day 180 | 57.3 RMS diaphragm (% of MIP) | Standard Deviation 38.9 |
Secondary
Maximal Inspiratory Pressure (MIP) at Baseline and Day 180
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.
Time frame: Baseline, Day 180
Population: Subjects 4 and 6 were unavailable for MIP testing at baseline; Subjects 1 and 3 were unavailable for MIP testing at 6 months.
| Arm | Measure | Group | Value (MEAN) |
|---|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Maximal Inspiratory Pressure (MIP) at Baseline and Day 180 | Baseline | 35.6 cm H2O |
| Pompe Subjects Receiving NeuRx DPS | Maximal Inspiratory Pressure (MIP) at Baseline and Day 180 | 180 Days | 32.7 cm H2O |
Other Pre-specified
Forced Expiratory Flow
Peak expiratory flow obtained during voluntary cough
Time frame: 180 days
Population: Only 2 patients were able to complete voluntary cough during a 180-day visit
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Forced Expiratory Flow | 42.65 L/min |
Other Pre-specified
Hours Per Day of Diaphragm Pacing
Number of hours used per day diaphragm pacing occurred by subjects
Time frame: 180 days
Population: Patients with Pompe disease who received diaphragm pacing
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Pompe Subjects Receiving NeuRx DPS | Hours Per Day of Diaphragm Pacing | 20.3 hours per day of diaphragm pacing |
Other Pre-specified
Magnetic Stimulation
EMG response to supramaximal bilateral stimulation of the phrenic nerves.
Time frame: 180 Days
Population: Magnetic stimulation was used as assessment for determining clinical eligibility for diaphragm pacing. It was not available at follow-up observational visits.
Other Pre-specified
Severe Respiratory Insufficiency Questionnaire
Patient reported measure of impact of respiratory insufficiency on functional mobility
Time frame: 180 days
Population: The Severe Respiratory Insufficiency Questionnaire was validated only in adults. Adults who participated did not complete the questionnaire at Day 180.