The Effectiveness of Roflumilast in Improving Mucociliary Clearance in Patients With COPD and Chronic Bronchitis

• Sponsor: Johns Hopkins University (Other)
• Overall Status: Completed
• CT.gov ID: NCT03073798
• Collaborator: (none)
• Enrollment: 12
• Arms: 2
• Actual Duration (Months): 25.9

Study Details

Study Description

Brief Summary

Specific Aim: To determine the effectiveness of Roflumilast in improving i) whole right lung and ii) peripheral right lung mucociliary clearance (MCC) in patients with COPD and chronic bronchitis.

Hypothesis: Roflumilast increases mucociliary clearance in patients with chronic bronchitis.

Study Design: This will be a double-blinded, cross-over randomized controlled trial with 1:1 randomization of 20 individuals with chronic bronchitis. Subjects will undergo baseline MCC then will be randomized to either roflumilast or placebo x 4 weeks, then there will be a 4 week wash-out phase and a second 4 week period of roflumilast/placebo depending on initial randomization. MCC will be conducted at baseline and at the end of each 4 week medication phase.

Condition or Disease	Intervention/Treatment	Phase
COPD; Chronic Bronchitis; Emphysema	Drug: Roflumilast; Drug: Placebo	Phase 4

Detailed Description

The purpose of this study is to investigate how well Roflumilast improves mucociliary clearance in people with chronic bronchitis. Several studies show that roflumilast may modulate (change) mucociliary function. This study is designed to determine if these favorable effects lead to improved mucociliary clearance (MCC) in people with chronic bronchitis, thereby, reducing the potential for acute infections and hospitalizations. Daliresp® (roflumilast) is a drug currently marketed (approved by the U.S. Food and Drug Administration (FDA) for use in humans) in the U.S. and is indicated (used) for treatment of people with severe COPD to treat the symptoms of cough and excess mucous linked to chronic bronchitis. Roflumilast is used to reduce the risk (chance) of COPD exacerbations (increase in symptoms such as cough, mucus secretions, and shortness of breath, that can be life threatening and reduces the ability to breathe) linked to chronic bronchitis (swelling of the airways in the lungs). Roflumilast is FDA approved to decrease the number of flare-ups of chronic obstructive pulmonary disease (COPD) in patients with severe COPD with chronic bronchitis and a history of flare-ups. The exact way Roflumilast does this is not known. Although Roflumilast is an FDA approved drug, in this study the drug is not being used for its FDA-approved indication.

If you agree to be in this study, you will receive no new COPD treatment other than the drugs provided for the study. You will also be given a tablet to take once a day, which will be placebo for at least part of the study. A placebo is a substance that looks like the study drug but that contains no active ingredients.

The study is a double-blind study. Double-blind means that neither you nor the study doctor will know which study regimen (roflumilast or placebo) you are receiving throughout the study. However, this information can be made available if medically necessary and as determined by the participant's study. You will undergo baseline mucociliary Clearance (MCC) Measurements then will be randomized (by chance, like the flip of a coin) to receive either roflumilast or placebo for 4 weeks, then there will be a 4 week wash-out phase, and a second 4 week period of roflumilast/placebo depending on initial randomization. Mucociliary Clearance (MCC) Measurements will be conducted at the beginning and at the end of each 4 week study regimen phase. You will be in the study for about 12 weeks and there will be up to 12 visits. At baseline, and prior to each MCC Procedure, you will have health assessments which may include Physical Examination, Health and Demographic Interview, Exhaled Carbon Monoxide (eCO) Testing, Spirometry (Breathing Test), Expectorated Sputum Collection, Pregnancy Testing and Mucociliary Clearance (MCC) Measurements.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effectiveness of Roflumilast in Improving Mucociliary Clearance in Patients With COPD and Chronic Bronchitis
• Actual Study Start Date: Mar 18, 2013
• Actual Primary Completion Date: May 14, 2015
• Actual Study Completion Date: May 14, 2015

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Medication Roflumilast. 500 mcg of Roflumilast daily for 4 weeks, then there will be a 4 week wash-out phase (no medication) and a second 4 week period of placebo.	Drug: Roflumilast; 500 mcg of Roflumilast which is a prescription medicine used in adults with severe COPD to decrease the number of flare-ups or the worsening of COPD symptoms; Other Names: Daliresp ; Drug: Placebo; 500 mcg of placebo is used; Other Names: Sugar Pill
Placebo Comparator: Placebo Placebo. 500 mcg of Placebo daily for 4 weeks, then there will be a 4 week wash-out phase (no medication) and a second 4 week period of Roflumilast	Drug: Roflumilast; 500 mcg of Roflumilast which is a prescription medicine used in adults with severe COPD to decrease the number of flare-ups or the worsening of COPD symptoms; Other Names: Daliresp ; Drug: Placebo; 500 mcg of placebo is used; Other Names: Sugar Pill

Outcome Measures

Primary Outcome Measures

1. Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A [Change from 0 to 30 minutes]

   Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.

2. Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A [Change from 0 to 60 minutes]

   Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.

3. Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A [Change from 0 to 90 minutes]

   Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.

4. Difference in Mucociliary Clearance (MCC) Between Visit 1B and Visit 2B [Change from 0 min to 24 hours]

   Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 40 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Physician diagnosis of COPD

• Forced Expiratory Volume in 1 second (FEV1) / Forced Vital Capacity (FVC) ≤70%

• FEV1 (% predicted) ≥40 % AND ≤ 70%,

• Tobacco exposure ≥ 10 pack-years,

• Chronic cough and sputum production

• At least one COPD exacerbation requiring systemic glucocorticosteroids or treatment in hospital, or both, in the previous year

• Not suffering from any concomitant disease that might interfere with study procedures or evaluations.

Exclusion Criteria:

• COPD exacerbation indicated by a treatment with systemic glucocorticosteroids and/or antibiotics not stopped at least 4 weeks prior to the baseline visit V0

• Lower respiratory tract infection not resolved 4 weeks prior to the baseline visit V0

• Diagnosis of asthma and/or other relevant lung disease (e.g. history of bronchiectasis, cystic fibrosis, bronchiolitis, lung resection, lung cancer, interstitial lung disease [e.g. fibrosis, silicosis, sarcoidosis], and active tuberculosis

• Known alpha-1-antitrypsin deficiency

• Known infection with HIV and/or active hepatitis

• Pregnancy or women of childbearing potential not using or willing to continue using a medically reliable method of contraception for the entire study period

• Suspected hypersensitivity to the study medication (roflumilast).

• Use of mucolytics within the last 4 weeks.

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• Johns Hopkins University

Investigators

• Principal Investigator: Nadia Hansel, MD MPH, Jonhs Hopkins University
• Principal Investigator: Beth Laube, PhD, Jonhs Hopkins University

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Johns Hopkins University
• ClinicalTrials.gov Identifier: NCT03073798
• Other Study ID Numbers: NA_00078710
• First Posted: Mar 8, 2017
• Last Update Posted: Jul 27, 2017
• Last Verified: Jun 1, 2017

• Keywords provided by Johns Hopkins University: Lung Disease; Breathing Difficulty; Smoking; Mucociliary
• Additional relevant MeSH terms: Bronchitis; Bronchitis, Chronic; Emphysema; Acute Disease

Study Results

Participant Flow

Arm/Group Title	All Participants
Arm/Group Description	Subjects underwent baseline MCC, then first received Roflumilast 500 mcg daily for 4 weeks. After a washout period of 4 weeks, they then received Placebo 500 mcg for an additional 4 weeks.
Period Title: Overall Study
STARTED	12
COMPLETED	10
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	All Participants
Arm/Group Description	Roflumilast. 500 mcg of Roflumilast daily for 4 weeks, then there will be a 4 week wash-out phase (no medication) and a second 4 week period of placebo. Roflumilast: 500 mcg of Roflumilast which is a prescription medicine used in adults with severe Chronic Obstructive Pulmonary Disease (COPD) to decrease the number of flare-ups or the worsening of COPD symptoms Placebo: 500 mcg of placebo is used
Overall Participants	12
Age (Count of Participants)
<=18 years	0 0%
Between 18 and 65 years	1 8.3%
>=65 years	11 91.7%
Sex: Female, Male (Count of Participants)
Female	5 41.7%
Male	7 58.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	1 8.3%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	2 16.7%
White	9 75%
More than one race	0 0%
Unknown or Not Reported	0 0%

Outcome Measures

1. Primary Outcome

Title	Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A
Description	Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.
Time Frame	Change from 0 to 30 minutes

Outcome Measure Data

Analysis Population Description

Data was not collected for all participants in this outcome measure due to lack of follow-up, patient withdrawal from the study, and an adverse event.

Arm/Group Title	All Roflumilast MCC	All Placebo MCC
Arm/Group Description	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on roflumilast.	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on placebo.
Measure Participants	9	10
Mean (Standard Deviation) [percentage difference of MCC]	-1.50 (3.76)	-0.70 (4.71)

2. Primary Outcome

Title	Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A
Description	Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.
Time Frame	Change from 0 to 60 minutes

Outcome Measure Data

Analysis Population Description

Data was not collected for all participants in this outcome measure due to lack of follow-up, patient withdrawal from the study, and an adverse event.

Arm/Group Title	All Roflumilast MCC	All Placebo MCC
Arm/Group Description	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on roflumilast.	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on placebo.
Measure Participants	9	10
Mean (Standard Deviation) [percentage difference of MCC]	-2.18 (5.17)	0.13 (5.81)

3. Primary Outcome

Title	Difference in Mucociliary Clearance (MCC) Between Visit 1A and Visit 2A
Description	Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.
Time Frame	Change from 0 to 90 minutes

Outcome Measure Data

Analysis Population Description

Data was not collected for all participants in this outcome measure due to lack of follow-up, patient withdrawal from the study, and an adverse event.

Arm/Group Title	All Roflumilast MCC	All Placebo MCC
Arm/Group Description	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on roflumilast.	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on placebo.
Measure Participants	9	10
Mean (Standard Deviation) [percentage difference of MCC]	-1.31 (7.77)	0.52 (6.63)

4. Primary Outcome

Title	Difference in Mucociliary Clearance (MCC) Between Visit 1B and Visit 2B
Description	Measurements of MCC (Mucociliary clearance) will be obtained using a large-field-of-view 2D gamma camera (Siemens Orbiter) following inhalation of a radioaerosol containing a gamma emitting isotope 99mtechnetium (99mTc)-sulfur-colloid. The total exposure to radiation from procedures associated with the MCC studies is similar to that of a chest x-ray and is much less than the 0.3 rem that the average person in the United States gets each year from natural sources like the sun, outer space, air, food, and soil. After inhaling (0 time point) an aerosol generated from a saline solution containing the radioisotope 99mtechnetium (99mTc)-sulfur-colloid (radioaerosol), subjects will sit with their back to a gamma camera. The gamma camera will acquire an image of where the isotopic marker initially deposits in the right lung at time 0 and how much remains in the lungs at the specified time point and will be measured in change of %/min from 0 min time point.
Time Frame	Change from 0 min to 24 hours

Outcome Measure Data

Analysis Population Description

Data was not collected for all participants in this outcome measure due to lack of follow-up, patient withdrawal from the study, and an adverse event.

Arm/Group Title	All Roflumilast MCC	All Placebo MCC
Arm/Group Description	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on roflumilast.	Taking into account the washout period and crossover design of this study, we are presenting the results to reflect all of the MCC studies done while the participants were on placebo.
Measure Participants	9	10
Mean (Standard Deviation) [percentage difference of MCC]	-0.13 (12.87)	6.93 (18.50)

Adverse Events

Arm/Group Title	All Participants
Arm/Group Description	Subjects underwent baseline MCC, then first received Roflumilast 500 mcg daily for 4 weeks. After a washout period of 4 weeks, they then received Placebo 500 mcg for an additional 4 weeks. MCC was conducted at baseline and at the end of each 4 week medication phase.
All Cause Mortality
	All Participants
	Affected / at Risk (%)	# Events
Total	0/12 (0%)
Serious Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)
Respiratory, thoracic and mediastinal disorders
Pulmonary Exacerbation	1/12 (8.3%)	1
Other (Not Including Serious) Adverse Events
	All Participants
	Affected / at Risk (%)	# Events
Total	0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.