Cystic Fibrosis, Mucociliary Clearance Defect
Conditions
Brief summary
This is a pilot study investigating the effectiveness and clinical efficacy of airway clearance therapy (ACT) in cystic fibrosis (CF). Enrolled subjects will undergo measurements of mucociliary clearance (MCC) and exhaled biomarkers at baseline and after 3 different forms of ACT: high frequency chest wall oscillatory vest, oscillatory positive expiratory pressure device, and whole-body vibration.
Interventions
OTHERBaseline (Huff-Cough alone)
Subjects will provide two huffs (forced expiratory maneuver with open glottis) followed by a cough every six minutes for a total of six Huff-Coughs.
DEVICEOscillatory Positive Expiatory Pressure Device
Subjects will use an Areobika® branded OPEP device (10 breaths through highest tolerated resistance) prior to undergoing a Huff-Cough. Subjects will use the device six times every six minutes.
DEVICEWhole-Body Vibration Platform
Subjects will be seated on a PowerPlate® whole-body vibration platform for 90 seconds prior to Huff-Cough. Six intervals on the platform will be completed six minutes apart.
DEVICEHigh Frequency Chest Wall Oscillatory Vest
Subjects will use TheVest® using a standardized Minnesota Protocol divided into six, four-minute segments, each followed by a Huff-Cough.
Sponsors
Cystic Fibrosis Foundation
University of North Carolina, Chapel Hill
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
BASIC_SCIENCE
Masking
NONE
Intervention model description
All subjects will undergo baseline testing, followed by study procedures for three separate interventions, with subjects randomized into three arms in which a different sequence in which to complete the studies.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Adults with confirmed diagnosis of cystic fibrosis aged 18 years and older.
Exclusion criteria
* Pregnant or lactating women, * Individuals with severe lung disease (FEV1 \<30%), or with exacerbations of lung disease requiring antibiotics or medication change within four weeks prior to enrolment. * Individuals unable to use vest-based HFCWO, OPEP device, or who require oxygen supplementation at rest. * Individuals with significant balance or gait impairment preventing them from tolerating being positioned on a vibrating platform.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Mucociliary Clearance-274 | 274 minutes | As described in the protocol, gamma scintigraphy was used to measure clearance of particles from the whole right lung region of interest over 274 minutes. The primary outcome for this study was the area under the particle clearance curve from time 0 to 274 minutes post-inhalation (normalized to time by dividing by 274) and expressed as a percent, representing total average rate of mucociliary clearance (MCC). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Mucociliary Clearance-90 | 90 minutes | As described in the protocol, gamma scintigraphy was used to measure clearance of particles from the whole right lung region of interest over 274 minutes. This outcome for this study was the area under the particle clearance curve from time 0 to 90 minutes post-inhalation (normalized to time by dividing by 90) and expressed as a percent, representing average rate of mucociliary clearance (MCC) over 90 minutes. |
| Change in Rate of MCC | pre-ACT (0-16 mins) and during ACT (16-50 mins) | Change in slope of particle clearance curve between pre intervention and ACT period. |
| Change in Fraction of Exhaled Nitric Oxide (FENO) | pre and immediately post intervention (50 mins post inhalation) | FENO measurements were obtained pre- and post- intervention. The difference of post- vs pre- ACT FENO was reported. |
| Purine Analysis (AMP) in Exhaled Breath Condensate | pre and immediately post intervention (50 mins post inhalation) | Exhaled breath condensate was collected using a commercial device for this purpose. Concentrations of the purine adenosine monophosphate (AMP) and urea in this liquid were determined using mass spectrometry. This outcome was the difference in concentrations of AMP normalized to urea in this exhaled breath condensate between post-ACT and pre-ACT intervention. |
| Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC) | pre and immediately post intervention (50 mins post inhalation) | Difference of concentration of adenosine (a purine) in EBC between post-ACT and pre-ACT intervention. |
| Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate | pre and immediately post intervention (50 mins post inhalation) | Difference of concentration of hypoxanthine (a purine) in Exhaled Breath Condensate between post-ACT and pre-ACT intervention. |
Countries
United States
Participant flow
Recruitment details
Patients were screened and recruited from the adult CF clinic at UNC from January 2017 to December 2017.
Pre-assignment details
Following screening, patients performed a baseline study visit prior to randomization into the study arms which determined which order to complete the other three interventions would be performed. Baseline (or huff-cough) was completed prior to randomization to ensure comparator data if a patient was unable to complete the study.
Participants by arm
| Arm | Count |
|---|---|
| Sequence A In this arm, the interventions were performed in the following order:
Baseline (prior to randomization), Whole body vibration, Vest, OPEP (note this is different than the sequence shown in the example latin square shown in the included protocol, as that was meant to serve as an example -- actual randomization and formulation of the employed latin square / sequence generator was performed following completion of the protocol) | 4 |
| Sequence B In this arm, the interventions were performed in the following order:
Baseline (prior to randomization), Vest, OPEP, Whole body vibration (note this is different than the sequence shown in the example latin square shown in the included protocol, as that was meant to serve as an example -- actual randomization and formulation of the employed latin square / sequence generator was performed following completion of the protocol) | 3 |
| Sequence C In this arm, the interventions were performed in the following order:
Baseline (prior to randomization), OPEP, Whole body vibration, Vest (note this is different than the sequence shown in the example latin square shown in the included protocol, as that was meant to serve as an example -- actual randomization and formulation of the employed latin square / sequence generator was performed following completion of the protocol) | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Sequence C | Total | Sequence A | Sequence B |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 10 Participants | 4 Participants | 3 Participants |
| Age, Continuous | 41 years | 40.5 years | 42.25 years | 37.67 years |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants | 2 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 8 Participants | 3 Participants | 3 Participants |
| Sex: Female, Male Female | 3 Participants | 7 Participants | 2 Participants | 2 Participants |
| Sex: Female, Male Male | 0 Participants | 3 Participants | 2 Participants | 1 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| other Total, other adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 | 0 / 10 | 0 / 10 |
Outcome results
Primary
Mucociliary Clearance-274
As described in the protocol, gamma scintigraphy was used to measure clearance of particles from the whole right lung region of interest over 274 minutes. The primary outcome for this study was the area under the particle clearance curve from time 0 to 274 minutes post-inhalation (normalized to time by dividing by 274) and expressed as a percent, representing total average rate of mucociliary clearance (MCC).
Time frame: 274 minutes
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Mucociliary Clearance-274 | 20.3 percent clearance | Standard Error 2.6 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Mucociliary Clearance-274 | 16.8 percent clearance | Standard Error 3.1 |
| Whole Body Vibration | Mucociliary Clearance-274 | 18.5 percent clearance | Standard Error 2.8 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Mucociliary Clearance-274 | 19.1 percent clearance | Standard Error 2.3 |
Comparison: No comparable preliminary data exists on mucociliary clearance (MCC) in response to airway clearance therapy methods (ACTs) for a power calculation. However, prior studies of medication effect on MCC gave a baseline mean change of Ave270 clr of 27.7% (std dev of 15.1%). Thus, the investigators estimated a mean change of 20% for effective ACT with the same estimate for variability (Std Dev of 15.1%). Using a paired 2-tailed test to compare means, 7 subjects were estimated to be needed.p-value: 0.615ANOVA
Secondary
Change in Fraction of Exhaled Nitric Oxide (FENO)
FENO measurements were obtained pre- and post- intervention. The difference of post- vs pre- ACT FENO was reported.
Time frame: pre and immediately post intervention (50 mins post inhalation)
Population: Only subjects who had measurable FENO above detection limits of the device (i.e. \<5 ppm) for both before and after ACT were included in analysis. Data from subjects during interventions who did not have a detectable FENO for both pre- and post- ACT were excluded for analysis.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Change in Fraction of Exhaled Nitric Oxide (FENO) | -1.84 ppm of NO | Standard Deviation 3.36 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Change in Fraction of Exhaled Nitric Oxide (FENO) | -1.81 ppm of NO | Standard Deviation 2.65 |
| Whole Body Vibration | Change in Fraction of Exhaled Nitric Oxide (FENO) | -1.42 ppm of NO | Standard Deviation 5.41 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Change in Fraction of Exhaled Nitric Oxide (FENO) | -.75 ppm of NO | Standard Deviation 1.8 |
Comparison: The investigators compared FENO before and after ACT in a pooled manner (i.e., grouping each of the comparisons together), as the study was not powered for FENO comparisons within each ACT type.p-value: 0.001t-test, 2 sided
Comparison: if the difference between pre and post-ACT FENO was significant (defined as p\<0.05), it was investigated whether change in FENO correlated with MCC (as represented by Ave90Clr)p-value: 0.692Regression, Linear
Secondary
Change in Rate of MCC
Change in slope of particle clearance curve between pre intervention and ACT period.
Time frame: pre-ACT (0-16 mins) and during ACT (16-50 mins)
Population: Only 4 subjects were included due to poor quality data obtained for slope measurement due to subject movement during the study (other MCC data used area under the curve data from key frames in which there was no subject movement, which proved to be more reliable). This data was not analyzed statistically.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Huff-Cough Alone | Change in Rate of MCC | 0.011 %clearance / minute |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Change in Rate of MCC | .013 %clearance / minute |
| Whole Body Vibration | Change in Rate of MCC | 0.011 %clearance / minute |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Change in Rate of MCC | 0.010 %clearance / minute |
Secondary
Mucociliary Clearance-90
As described in the protocol, gamma scintigraphy was used to measure clearance of particles from the whole right lung region of interest over 274 minutes. This outcome for this study was the area under the particle clearance curve from time 0 to 90 minutes post-inhalation (normalized to time by dividing by 90) and expressed as a percent, representing average rate of mucociliary clearance (MCC) over 90 minutes.
Time frame: 90 minutes
Population: All subjects were included for analysis
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Mucociliary Clearance-90 | 13.8 percent clearance | Standard Deviation 6.2 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Mucociliary Clearance-90 | 12.6 percent clearance | Standard Deviation 5.9 |
| Whole Body Vibration | Mucociliary Clearance-90 | 12.4 percent clearance | Standard Deviation 7.3 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Mucociliary Clearance-90 | 12.8 percent clearance | Standard Deviation 6.9 |
p-value: 0.696ANOVA
Secondary
Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC)
Difference of concentration of adenosine (a purine) in EBC between post-ACT and pre-ACT intervention.
Time frame: pre and immediately post intervention (50 mins post inhalation)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC) | -0.042 unitless ratio (adenosine/Urea conc.) | Standard Deviation 0.166 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC) | -0.027 unitless ratio (adenosine/Urea conc.) | Standard Deviation 0.065 |
| Whole Body Vibration | Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC) | -0.057 unitless ratio (adenosine/Urea conc.) | Standard Deviation 0.134 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Purine Analysis (Adenosine) in Exhaled Breath Condensate (EBC) | -.005 unitless ratio (adenosine/Urea conc.) | Standard Deviation 0.057 |
Comparison: The study was not designed or powered to assess for inter-group differences between the types of ACT, and for analytical purposes, these were pooled, with the analysis being a paired comparison within subjects to pre- to post-ACT.p-value: 0.041Wilcoxon signed-rank test
Comparison: If the difference between pre and post-ACT adenosine (purine) in EBC was significant (defined as p\<0.05), the correlation between change in adenosine concentration and MCC (as represented by Ave90Clr) was investigated.p-value: 0.047Regression, Linear
Secondary
Purine Analysis (AMP) in Exhaled Breath Condensate
Exhaled breath condensate was collected using a commercial device for this purpose. Concentrations of the purine adenosine monophosphate (AMP) and urea in this liquid were determined using mass spectrometry. This outcome was the difference in concentrations of AMP normalized to urea in this exhaled breath condensate between post-ACT and pre-ACT intervention.
Time frame: pre and immediately post intervention (50 mins post inhalation)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Purine Analysis (AMP) in Exhaled Breath Condensate | -0.206 unitless ratio (AMP/Urea conc.) | Standard Deviation 0.679 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Purine Analysis (AMP) in Exhaled Breath Condensate | -.101 unitless ratio (AMP/Urea conc.) | Standard Deviation 0.124 |
| Whole Body Vibration | Purine Analysis (AMP) in Exhaled Breath Condensate | -.036 unitless ratio (AMP/Urea conc.) | Standard Deviation 0.65 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Purine Analysis (AMP) in Exhaled Breath Condensate | 0.144 unitless ratio (AMP/Urea conc.) | Standard Deviation 0.406 |
Comparison: The study was not designed or powered to assess for inter-group differences between the types of ACT, and for analytical purposes, these were pooled, with the analysis being a paired comparison within subjects to pre- to post-ACT.p-value: 0.146Wilcoxon signed-rank test
Secondary
Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate
Difference of concentration of hypoxanthine (a purine) in Exhaled Breath Condensate between post-ACT and pre-ACT intervention.
Time frame: pre and immediately post intervention (50 mins post inhalation)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Huff-Cough Alone | Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate | -1.04 unitless ratio (adenosine/Urea conc.) | Standard Deviation 6.03 |
| Oscillatory Positive Expiatory Pressure Device (OPEP) | Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate | -1.93 unitless ratio (adenosine/Urea conc.) | Standard Deviation 4.16 |
| Whole Body Vibration | Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate | 1.64 unitless ratio (adenosine/Urea conc.) | Standard Deviation 7.81 |
| High Frequency Chest Wall Oscillatory Vest (HFCWO) | Purine Analysis (Hypoxanthine) in Exhaled Breath Condensate | 0.760 unitless ratio (adenosine/Urea conc.) | Standard Deviation 1.88 |
Comparison: The study was not designed or powered to assess for inter-group differences between the types of ACT, and for analytical purposes, these were pooled, with the analysis being a paired comparison within subjects to pre- to post-ACT.p-value: 0.07Wilcoxon signed-rank test