KetoRLB: Effect of Ketoconazole on Breathlessness

• Sponsor: Dartmouth-Hitchcock Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT01378520
• Collaborator: (none)
• Enrollment: 20
• Location: 1
• Arms: 2
• Duration (Months): 8
• Patients Per Site Per Month: 2.5

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Chronic Obstructive Pulmonary Disease	Drug: ketoconazole; Drug: inert powder	Phase 4

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 20 participants
• Allocation: Randomized
• Intervention Model: Crossover Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: The Effect of Ketoconazole on Breathlessness During Resistive Load Breathing in Patients With Chronic Obstructive Pulmonary Disease
• Study Start Date: Jun 1, 2011
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Feb 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ketoconazole 600 mg ketoconazole	Drug: ketoconazole; 600 mg capsule oral once; Other Names: oral antifungal
Placebo Comparator: inert powder inert powder in capsule	Drug: inert powder; oral once; Other Names: oral placebo

Outcome Measures

Primary Outcome Measures

1. 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".

2. 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 Outcome Measures

1. 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

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years and Older
• Sexes Eligible for Study: All
• Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Dartmouth-Hitchcock Medical Center	Lebanon	New Hampshire	United States	03756-0001

Sponsors and Collaborators

• Dartmouth-Hitchcock Medical Center

Investigators

• Principal Investigator: Donald A Mahler, MD, Dartmouth-Hitchcock Medical Center

Study Documents (Full-Text)

None provided.

More Information

Publications

• Gifford AH, Mahler DA, Waterman LA, Ward J, Kraemer WJ, Kupchak BR, Baird JC. Neuromodulatory effect of endogenous opioids on the intensity and unpleasantness of breathlessness during resistive load breathing in COPD. COPD. 2011 Jun;8(3):160-6. doi: 10.3109/15412555.2011.560132. Epub 2011 Apr 22.

• Responsible Party: Dartmouth-Hitchcock Medical Center
• ClinicalTrials.gov Identifier: NCT01378520
• Other Study ID Numbers: CPHS22775
• First Posted: Jun 22, 2011
• Last Update Posted: Jun 1, 2018
• Last Verified: May 1, 2018

• Keywords provided by Dartmouth-Hitchcock Medical Center: breathlessness; resistive load breathing; beta-endorphins
• Additional relevant MeSH terms: Lung Diseases; Lung Diseases, Obstructive; Pulmonary Disease, Chronic Obstructive; Dyspnea; Ketoconazole

Study Results

Participant Flow

Recruitment Details	June 2011 - January 2012; medical center
Pre-assignment Detail	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))

Arm/Group Title	First Ketoconazole, Then Inert Powder	First Inert Powder, Then Ketoconazole
Arm/Group Description	Ketoconzaole (600 mg taken orally) in first intervention period and inert powder (in capsule taken orally) in second intervention period.	Inert powder (in capsule taken orally) in first intervention period and Ketoconzaole (600 mg taken orally) in second intervention period.
Period Title: First Intervention (Day 2-3)
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0
Period Title: First Intervention (Day 2-3)
STARTED	10	10
COMPLETED	10	10
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	Entire Study Population
Arm/Group Description	Includes groups randomized to receive Ketoconazole first and inert powder first.
Overall Participants	20
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69.6 (6.9)
Sex: Female, Male (Count of Participants)
Female	10 50%
Male	10 50%
Region of Enrollment (participants) [Number]
United States	20 100%

Outcome Measures

1. Primary Outcome

Title	Unpleasantness of Breathlessness
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketoconazole	Inert Powder
Arm/Group Description	Ketoconazole (600 mg given orally)	Inert powder (in capsule taken orally)
Measure Participants	20	20
Mean (Standard Deviation) [units on a scale]	72.5 (23.8)	72.6 (23.5)

2. Primary Outcome

Title	Intensity of Breathlessness
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketoconazole	Inert Powder
Arm/Group Description	Ketoconazole (600 mg given orally)	Inert powder (in capsule taken orally)
Measure Participants	20	20
Mean (Standard Deviation) [units on a scale]	77.6 (22.3)	78.2 (21.4)

3. Secondary Outcome

Title	Change in Level of B-endorphin Immunoreactivity
Description	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)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Ketoconazole	Inert Powder
Arm/Group Description	Ketoconazole (600 mg given orally)	Inert powder (in capsule taken orally)
Measure Participants	20	20
Mean (Standard Deviation) [pmol/L]	153.9 (18.0)	93.9 (7.9)

Adverse Events

Arm/Group Title	Ketoconazole		Inert Powder
Arm/Group Description	Ketoconazole(600 mg taken orally)		Inert powder (in capsule taken orally)
All Cause Mortality
	Ketoconazole		Inert Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Ketoconazole		Inert Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)
Other (Not Including Serious) Adverse Events
	Ketoconazole		Inert Powder
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/10 (0%)		0/10 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT 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.