Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA)

• Sponsor: Milton S. Hershey Medical Center (Other)
• Overall Status: Completed
• CT.gov ID: NCT00318708
• Collaborator: National Heart, Lung, and Blood Institute (NHLBI) (NIH)
• Enrollment: 92
• Locations: 10
• Arms: 2
• Duration (Months): 34
• Patients Per Site: 9.2
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Asthma can be caused by a variety of factors, including tobacco smoke, allergens, and respiratory airway infections. Many people use inhaled corticosteroid medications to treat their symptoms. These medications, however, are not effective for everyone. Clarithromycin is an antibiotic that may effectively treat asthma in these individuals. This study will evaluate the effectiveness of clarithromycin at controlling asthma symptoms.

Condition or Disease	Intervention/Treatment	Phase
Asthma	Drug: clarithromycin; Drug: fluticasone propionate; Drug: placebo clarithromycin	Phase 3

Detailed Description

Asthma prevalence has steadily increased in the United States since the early 1980s; currently, more than 20 million people are diagnosed with asthma. Individuals with this disease may experience periodic attacks of wheezing, shortness of breath, chest tightness, and coughing. While there are many known causes of asthma, including tobacco smoke and other allergens, the exact cause of some asthma cases remains unknown. Research has shown that in some individuals, respiratory airway infections may play a role in the onset and severity of the disease. Inhaled corticosteroids are commonly used to treat asthma; however, they do not effectively control symptoms for everyone. Clarithromycin, an antibiotic medication used to treat bacterial infections, may be an effective asthma treatment for individuals who do not respond well to inhaled corticosteroids. The purpose of this study is to evaluate the effectiveness of clarithromycin at reducing asthma symptoms.

This study will begin with a 4-week run-in period to standardize participants' asthma medication usage. During this time, all participants will stop their current asthma medications and instead will receive inhaled fluticasone twice a day. Albuterol will be available as a rescue medication if necessary. Study visits will take place every 2 weeks. Blood and saliva samples will be obtained for laboratory tests and participants will complete standardized questionnaires to assess asthma symptoms and quality of life. Spirometry will be performed to measure lung function. Medication adherence will be monitored with a daily diary and an electronic pill counting device. At the end of Week 4, participants will be evaluated for study eligibility. If eligible, participants will undergo a bronchoscopy and a lung biopsy to test for Mycoplasma pneumoniae and Chlamydia pneumoniae, two bacteria that have been identified as possible factors in the development of asthma.

The treatment phase of the study will last 16 weeks. Participants will be randomly assigned to receive either 500 mg of clarithromycin or placebo twice a day, plus inhaled fluticasone. At monthly study visits, spirometry and blood collection will be performed. Standardized questionnaires to assess asthma symptoms will be completed every 2 weeks. Medical adherence will continue to be monitored. At the end of Week 16, participants will stop receiving clarithromycin or placebo, but will continue to receive fluticasone. Asthma symptoms, rescue medication usage, quality of life, and lung capacity will be assessed; tissue samples will be examined for the presence of Mycoplasma pneumoniae and Chlamydia pneumoniae. An 8-week washout period will follow to observe any lingering medication effects and to monitor for safety. Monthly study visits during this period will include spirometry and blood collection.

Study Design

• Study Type: Interventional
• Actual Enrollment: 92 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Asthma Clinical Research Network (ACRN) Trial - Macrolides in Asthma (MIA)
• Study Start Date: Jun 1, 2006
• Actual Primary Completion Date: Apr 1, 2009
• Actual Study Completion Date: Apr 1, 2009

Arms and Interventions

Arm	Intervention/Treatment
Experimental: clarithromycin + fluticasone clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	Drug: clarithromycin; clarithromycin 500 mg twice daily (Biaxin); Other Names: Biaxin ; Drug: fluticasone propionate; fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily); Other Names: Flovent®
Active Comparator: placebo + fluticasone placebo clarithromycin twice daily + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	Drug: fluticasone propionate; fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily); Other Names: Flovent® ; Drug: placebo clarithromycin; placebo clarithromycin twice daily; Other Names: placebo Biaxin

Outcome Measures

Primary Outcome Measures

1. Juniper Asthma Control Questionnaire (ACQ) Results [Measured every four weeks during the 16-week treatment period, with the change (week 16 minus baseline) as the primary outcome]

   The Juniper asthma control questionnaire (ACQ) consists of six questions answered by the asthma patient with respect to symptoms, rescue medication use, and night-time awakenings due to asthma. A seventh item in the ACQ is the percent predicted FEV1. Each of the seven items is scored from from 0 (best) to 6 (worst), and then the seven items are averaged to yield a number from 0 (best) to 6 (worst). Asthma patients needed to display an ACQ greater than or equal to 1.25 in order to be eligible for randomization. A reduction of 0.5 units or more in the ACQ over the 16 weeks of treatment is considered to be clinically significant.

Secondary Outcome Measures

1. Asthma Rescue Medication Use [the week-16 average minus the baseline-week average]

   number of rescue puffs per day

2. AM Peak Expiratory Flow (PEF) [the week-16 average minus the baseline-week average]

   daily AM peak expiratory flow (PEF) measured in liters per minute

3. Forced Expiratory Volume in One Second (FEV1) [the week-16 value minus the baseline-value]

   Forced expiratory volume in one second (FEV1) from spirometry

4. Methacholine Provocative Concentration (PC20) [the week-16 value minus the baseline-value]

   Logarithm-base 2 transformed Methacholine provocative concentration (PC20) based on FEV1

5. Exhaled Nitric Oxide (eNO) [the week-16 value minus the baseline-value]

   Exhaled nitric oxide (eNO) measured in parts per billion

6. Asthma Quality of Life Questionnaire (AQLQ) [the week-16 value minus the baseline-value]

   The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 questions, with each question ranging from 1 (worst) to 7 (best). The 32 questions are averaged to yield an overall score, which is reported here. Therefore, a positive change between the 16-week score and the baseline score represents improvement.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 60 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• History of physician-diagnosed asthma

• Methacholine PC20 less than or equal to 16 mg/ml and/or FEV1 improvement greater than or equal to 12% in response to 180 mcg albuterol

• Stable asthma for at least 6 weeks prior to study entry

• FEV1 greater than or equal to 60% of predicted result following 180 mcg albuterol

• Juniper ACQ score greater than or equal to 1.5 (optimal ACQ score cut-off point for asthma that is "not well-controlled" by NIH/Global Initiative for Asthma [GINA] guidelines)

• Nonsmoker (less than 10 pack-per-year lifetime smoking history and no smoking in the year prior to study entry)

• Able to perform spirometry, as per American Thoracic Society criteria

• 75% adherence with diary cards, fluticasone (monitored with Doser), and placebo pill trial (monitored electronically with Electronic Drug Exposure Monitor [eDEM] pill dose counter) for the final 2 weeks of the four-week run-in period

• At Visit 1, in steroid-naïve participants, no significant adrenal suppression, defined as a plasma cortisol concentration less than 5 mcg/dL. If adrenal suppression occurs, a 250 mcg corticotropin (ACTH) stimulation test will be performed. Plasma cortisol levels will be collected at baseline, and 30 and 60 minutes after the ACTH stimulation test. Participants must have a cortisol concentration greater than 20 mcg/dL on at least one of the post-ACTH time points

• Absence of bronchoscopy-induced exacerbation; if bronchoscopy-induced exacerbation has occurred, prednisone therapy must have stopped at least 6 weeks prior to study entry

• Absence of respiratory tract infection; if infection has occurred, infection-related symptoms must have stopped at least 6 weeks prior to study entry

• Has experienced no more than two exacerbations or respiratory tract infections prior to study entry

• If female and able to conceive, willing to utilize two medically acceptable forms of contraception (one non-barrier method with single barrier method OR double barrier method)

Exclusion Criteria:

• Presence of lung disease other than asthma

• Presence of vocal cord dysfunction, due to potential confounding of ACQ score

• Significant medical illness other than asthma

• History of atrial or ventricular tachyarrhythmia

• Use of any medication that has a significant interaction with clarithromycin, including herbal or alternative therapies

• Asthma exacerbation within 6 weeks of the screening visit or during the run-in period prior to bronchoscopy

• Use of systemic steroids or change in dose of controller therapy within 6 weeks of the screening visit

• Inability, in the opinion of the study investigator, to coordinate use of dry powder or metered-dose inhaler or to comply with medication regimens

• Inability or unwillingness to perform required study procedures

• Prolonged heart rate corrected QT-interval (greater than 450 msec in women and greater than 430 msec in men) on echocardiogram (ECG) at study entry

• Low potassium or magnesium levels (based on local Asthma Clinical Research Network laboratory definitions)

• Abnormal elevation of liver function tests (AST, ALT, total bilirubin, or alkaline phosphatase)

• Abnormal prothrombin time (PT) or partial thromboplastin time (PTT) results

• Reduced creatinine clearance

• Contraindication to bronchoscopy, as determined by medical history or physical examination

• Regular consumption of grapefruit or grapefruit juice

• Pregnant or breastfeeding

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California, San Diego	San Diego	California	United States	92093
2	University of California, San Francisco	San Francisco	California	United States	94143
3	National Jewish Medical and Research Center	Denver	Colorado	United States	80206
4	Brigham & Women's Hospital	Boston	Massachusetts	United States	02115
5	Washington University, St. Louis	Saint Louis	Missouri	United States	63130
6	Columbia University Medical Center	New York	New York	United States	10032
7	Duke University Medical Center	Durham	North Carolina	United States	27710
8	Wake Forest University Health Sciences	Winston-Salem	North Carolina	United States	27157
9	University of Texas Medical Branch	Galveston	Texas	United States	77555
10	University of Wisconsin, Madison	Madison	Wisconsin	United States	53706

Sponsors and Collaborators

• Milton S. Hershey Medical Center
• National Heart, Lung, and Blood Institute (NHLBI)

Investigators

• Principal Investigator: William J. Calhoun, MD, University of Texas, Galveston
• Principal Investigator: Mario Castro, MD, Washington University School of Medicine
• Principal Investigator: Robert F. Lemanske, MD, University of Wisconsin, Madison
• Principal Investigator: Richard J. Martin, MD, National Jewish Health
• Principal Investigator: Elliot Israel, MD, Brigham and Women's Hospital
• Principal Investigator: Stephen P. Peters, MD, PhD, Wake Forest University Health Sciences
• Principal Investigator: Homer A. Boushey, MD, University of California, San Francsico
• Principal Investigator: Stephen I. Wasserman, MD, University of California, San Diego
• Principal Investigator: Emily DiMango, MD, Columbia University
• Principal Investigator: Monica Kraft, MD, Duke University
• Study Chair: Reuben M Cherniack, MD, National Jewish Health

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Click here for the Asthma Clinical Research Network (ACRN) web site

Publications

None provided.

• Responsible Party: Vernon M. Chinchilli, PhD, Distinguished Professor and Chair, Department of Public Health Sciences, Milton S. Hershey Medical Center
• ClinicalTrials.gov Identifier: NCT00318708
• Other Study ID Numbers: 377; U10HL074231; 5U10HL074231; 7U10HL074206; 5U10HL074208; 5U10HL074073; 5U10HL074227; 5U10HL074225; 5U10HL074204; 5U10HL074218; 5U10HL074212
• First Posted: Apr 27, 2006
• Last Update Posted: Mar 23, 2018
• Last Verified: Mar 1, 2018

• Additional relevant MeSH terms: Asthma; Fluticasone; Xhance; Clarithromycin

Study Results

Participant Flow

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Period Title: Overall Study
STARTED	47	45
8-week Milestone	42	42
COMPLETED	39	40
NOT COMPLETED	8	5

Baseline Characteristics

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone	Total
Arm/Group Description	Clarithromycin 500 mg bid (Biaxin) + fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)	Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)	Total of all reporting groups
Overall Participants	47	45	92
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	47 100%	45 100%	92 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	41.3 (12.5)	37.5 (10.5)	39.5 (11.5)
Sex: Female, Male (Count of Participants)
Female	27 57.4%	25 55.6%	52 56.5%
Male	20 42.6%	20 44.4%	40 43.5%
Region of Enrollment (participants) [Number]
United States	47 100%	45 100%	92 100%

Outcome Measures

1. Primary Outcome

Title	Juniper Asthma Control Questionnaire (ACQ) Results
Description	The Juniper asthma control questionnaire (ACQ) consists of six questions answered by the asthma patient with respect to symptoms, rescue medication use, and night-time awakenings due to asthma. A seventh item in the ACQ is the percent predicted FEV1. Each of the seven items is scored from from 0 (best) to 6 (worst), and then the seven items are averaged to yield a number from 0 (best) to 6 (worst). Asthma patients needed to display an ACQ greater than or equal to 1.25 in order to be eligible for randomization. A reduction of 0.5 units or more in the ACQ over the 16 weeks of treatment is considered to be clinically significant.
Time Frame	Measured every four weeks during the 16-week treatment period, with the change (week 16 minus baseline) as the primary outcome

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Measure Participants	39	39
Least Squares Mean (Standard Error) [units on a scale]	-0.15 (0.14)	-0.38 (0.14)

2. Secondary Outcome

Title	Asthma Rescue Medication Use
Description	number of rescue puffs per day
Time Frame	the week-16 average minus the baseline-week average

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily) clarithromycin: clarithromycin 500 mg twice daily (Biaxin) fluticasone propionate: fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin twice daily + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily) fluticasone propionate: fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily) placebo clarithromycin: placebo clarithromycin twice daily
Measure Participants	39	39
Least Squares Mean (Standard Error) [rescue puffs per day]	-0.71 (0.23)	-0.14 (0.24)

3. Secondary Outcome

Title	AM Peak Expiratory Flow (PEF)
Description	daily AM peak expiratory flow (PEF) measured in liters per minute
Time Frame	the week-16 average minus the baseline-week average

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Measure Participants	39	39
Least Squares Mean (Standard Error) [liters per minute]	8.31 (4.55)	11.69 (4.48)

4. Secondary Outcome

Title	Forced Expiratory Volume in One Second (FEV1)
Description	Forced expiratory volume in one second (FEV1) from spirometry
Time Frame	the week-16 value minus the baseline-value

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Measure Participants	39	39
Least Squares Mean (Standard Error) [Liters]	-0.08 (0.05)	-0.06 (0.06)

5. Secondary Outcome

Title	Methacholine Provocative Concentration (PC20)
Description	Logarithm-base 2 transformed Methacholine provocative concentration (PC20) based on FEV1
Time Frame	the week-16 value minus the baseline-value

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Measure Participants	39	39
Least Squares Mean (Standard Error) [logarithm-base 2 of mg/mL]	1.39 (0.30)	0.41 (0.30)

6. Secondary Outcome

Title	Exhaled Nitric Oxide (eNO)
Description	Exhaled nitric oxide (eNO) measured in parts per billion
Time Frame	the week-16 value minus the baseline-value

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	clarithromycin 500 mg twice daily (Biaxin) + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)	placebo clarithromycin + fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)
Measure Participants	39	39
Least Squares Mean (Standard Error) [parts per billion]	-0.33 (3.16)	3.04 (3.26)

7. Secondary Outcome

Title	Asthma Quality of Life Questionnaire (AQLQ)
Description	The Asthma Quality of Life Questionnaire (AQLQ) consists of 32 questions, with each question ranging from 1 (worst) to 7 (best). The 32 questions are averaged to yield an overall score, which is reported here. Therefore, a positive change between the 16-week score and the baseline score represents improvement.
Time Frame	the week-16 value minus the baseline-value

Outcome Measure Data

Analysis Population Description

The number of participants for the analysis was determined as the number who completed the full 16 weeks (value at 16 weeks minus value at baseline).

Arm/Group Title	Clarithromycin + Fluticasone	Placebo + Fluticasone
Arm/Group Description	Clarithromycin 500 mg bid (Biaxin) + fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)	Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)
Measure Participants	39	39
Least Squares Mean (Standard Error) [units on a scale (1 through 7)]	0.41 (0.16)	0.59 (0.15)

Adverse Events

Time Frame	6 months
Adverse Event Reporting Description	does not differ from clinicaltrials.gov definitions
Arm/Group Title	Clarithromycin + Fluticasone		Placebo + Fluticasone
Arm/Group Description	Clarithromycin 500 mg bid (Biaxin) + fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)		Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)
All Cause Mortality
	Clarithromycin + Fluticasone		Placebo + Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Clarithromycin + Fluticasone		Placebo + Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/47 (0%)		0/45 (0%)
Other (Not Including Serious) Adverse Events
	Clarithromycin + Fluticasone		Placebo + Fluticasone
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	9/47 (19.1%)		7/45 (15.6%)
Gastrointestinal disorders
gastrointestinal events	7/47 (14.9%)	9	3/45 (6.7%)	5
Respiratory, thoracic and mediastinal disorders
respiratory infections	5/47 (10.6%)	5	5/45 (11.1%)	5

Limitations/Caveats

Participants underwent endobronchial biopsy for characterization of lower airway status for M pneumoniae or C pneumoniae. The target sample size was 72 positives and 72 negatives. Only 80 and 12 were recruited, respectively.

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.