Chronic Obstructive Pulmonary Disease
Conditions
Keywords
breathlessness, resistive load breathing, beta-endorphins
Brief summary
Beta-endorphins, which are naturally occurring narcotic substances, have been shown to alter the perception of breathlessness. Oral ketoconazole, an antifungal antibiotic, increases blood levels of beta-endorphins. The study hypothesis is that oral ketoconazole will reduce ratings of breathlessness induced by resistive breathing loads.
Detailed description
Beta-endorphins are naturally occurring narcotic substances (like morphine) that are released by the brain under stressful conditions, such as exercise and when breathing through a resistive load (a tube containing fine wire mesh). In one study of 8 patients with coronary artery disease, ketoconazole, an oral medication used to treat fungal infections, was administered (1,200 mg at 12 midnight and 600 mg at 6 am) and increased blood levels of beta-endorphins five fold. In a recent study performed at Dartmouth-Hitchcock Medical Center, we found that ketoconazole increased blood levels of beta-endorphins in all eight patients with chronic obstructive pulmonary disease (COPD). Mean values increased by 2.5 times at four hours compared with baseline values (p = 0.0078). Based on this significant response, we propose to study the effect of ketoconazole on patients' perception of breathlessness induced by resistive breathing loads in a randomized clinical trial. The hypothesis of the study is that ketoconazole will reduce ratings of breathlessness as mediated by the increased levels of beta-endorphins.
Interventions
DRUGketoconazole
600 mg capsule oral once
DRUGinert powder
oral once
Sponsors
Dartmouth-Hitchcock Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
50 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* 50 years of age or older; * diagnosis of COPD; * current or former smoker of at least 10 pack-years; * post-bronchodilator FEV1 greater than or equal to 30% predicted and less than or equal to 80% predicted; post-bronchodilator ratio \< 70%
Exclusion criteria
* any concomitant disease that might interfere with study procedures; * use of a drug that may cause a possible drug interaction with ketoconazole
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Unpleasantness of Breathlessness | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) | The average of all ratings for the unpleasantness of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for unpleasantness through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of unpleasantness was obtained during RLB on a 100 mm Visual Analog Scale anchored at the bottom by No Unpleasantness and at the top by Greatest Unpleasantness. |
| Intensity of Breathlessness | At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7) | The average of all ratings for the intensity of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of breathlessness was obtained at 1 minute intervals during RLB on a 100 mm Visual Analog Scale anchored at the bottom by No Intensity and at the top by Greatest Intensity. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Level of B-endorphin Immunoreactivity | At the end of resistance load breathing (4.5 hours after receiving the test article) | Change between pre-treatment and post treatment serum levels of beta-endorphin immunoreactivity measured in pmol/L |
Countries
United States
Participant flow
Recruitment details
June 2011 - January 2012; medical center
Pre-assignment details
23 subjects recruited; 1 excluded (did not meet inclusion/exclusion criteria); 2 withdrawn prior to randomization (1 could not tolerate breathing through the initial inspiratory resistance (15 cm H 2 O/L/s); 1 gave ratings of breathlessness of \< 50 mm on the VAS for the highest resistance (50 cm H2O/L/s))
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to receive Ketoconazole first and inert powder first. | 20 |
| Total | 20 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Continuous | 69.6 years STANDARD_DEVIATION 6.9 |
| Region of Enrollment United States | 20 participants |
| Sex: Female, Male Female | 10 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 10 | 0 / 10 |
| serious Total, serious adverse events | 0 / 10 | 0 / 10 |
Outcome results
Primary
Intensity of Breathlessness
The average of all ratings for the intensity of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for intensity through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of breathlessness was obtained at 1 minute intervals during RLB on a 100 mm Visual Analog Scale anchored at the bottom by No Intensity and at the top by Greatest Intensity.
Time frame: At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketoconazole | Intensity of Breathlessness | 77.6 units on a scale | Standard Deviation 22.3 |
| Inert Powder | Intensity of Breathlessness | 78.2 units on a scale | Standard Deviation 21.4 |
Primary
Unpleasantness of Breathlessness
The average of all ratings for the unpleasantness of breathlessness at equivalent times for each subject during Resistive Load Breathing (RLB). For example, if 1 subject provided 6 ratings during 6 minutes of RLB with Ketoconazole and 10 ratings during 10 minutes of RLB with inert powder, then ratings for unpleasantness through 6 minutes were used for analysis for that patient. This approach was used for all subjects to yield a total of 252 ratings for Ketoconazole and for inert powder. Subject rating of intensity of unpleasantness was obtained during RLB on a 100 mm Visual Analog Scale anchored at the bottom by No Unpleasantness and at the top by Greatest Unpleasantness.
Time frame: At 1 minute intervals during Resistive Load Breathing at Period 1 (Day 3 or 4) and Period 2 (Day 5, 6 or 7)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketoconazole | Unpleasantness of Breathlessness | 72.5 units on a scale | Standard Deviation 23.8 |
| Inert Powder | Unpleasantness of Breathlessness | 72.6 units on a scale | Standard Deviation 23.5 |
Secondary
Change in Level of B-endorphin Immunoreactivity
Change between pre-treatment and post treatment serum levels of beta-endorphin immunoreactivity measured in pmol/L
Time frame: At the end of resistance load breathing (4.5 hours after receiving the test article)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Ketoconazole | Change in Level of B-endorphin Immunoreactivity | 153.9 pmol/L | Standard Deviation 18 |
| Inert Powder | Change in Level of B-endorphin Immunoreactivity | 93.9 pmol/L | Standard Deviation 7.9 |