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

Status

Completed

Phases

Phase 3

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT00318708

Acronym

MIA

Enrollment

Registered

2006-04-27

Start date

2006-06-30

Completion date

2009-04-30

Last updated

2018-03-23

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Asthma

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.

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.

Interventions

DRUGclarithromycin

clarithromycin 500 mg twice daily (Biaxin)

DRUGfluticasone propionate

fluticasone propionate 88 mcg twice daily (Flovent® HFA 44 mcg two puffs twice daily)

DRUGplacebo clarithromycin

placebo clarithromycin twice daily

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to 60 Years

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
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

Measure	Time frame	Description
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
Forced Expiratory Volume in One Second (FEV1)	the week-16 value minus the baseline-value	Forced expiratory volume in one second (FEV1) from spirometry
Asthma Rescue Medication Use	the week-16 average minus the baseline-week average	number of rescue puffs per day
Exhaled Nitric Oxide (eNO)	the week-16 value minus the baseline-value	Exhaled nitric oxide (eNO) measured in parts per billion
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.
Methacholine Provocative Concentration (PC20)	the week-16 value minus the baseline-value	Logarithm-base 2 transformed Methacholine provocative concentration (PC20) based on FEV1

Countries

United States

Participant flow

Participants by arm

Arm	Count
Clarithromycin + Fluticasone Clarithromycin 500 mg bid (Biaxin) + fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)	47
Placebo + Fluticasone Fluticasone propionate 88 mcg bid (Flovent® HFA 44 mcg two puffs bid)	45
Total	92

Baseline characteristics

Characteristic	Placebo + Fluticasone	Clarithromycin + Fluticasone	Total
Age, Categorical <=18 years	0 Participants	0 Participants	0 Participants
Age, Categorical >=65 years	0 Participants	0 Participants	0 Participants
Age, Categorical Between 18 and 65 years	45 Participants	47 Participants	92 Participants
Age, Continuous	37.5 years STANDARD_DEVIATION 10.5	41.3 years STANDARD_DEVIATION 12.5	39.5 years STANDARD_DEVIATION 11.5
Region of Enrollment United States	45 participants	47 participants	92 participants
Sex: Female, Male Female	25 Participants	27 Participants	52 Participants
Sex: Female, Male Male	20 Participants	20 Participants	40 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk
deaths Total, all-cause mortality	— / —	— / —
other Total, other adverse events	9 / 47	7 / 45
serious Total, serious adverse events	0 / 47	0 / 45

Outcome results

Primary

Juniper Asthma Control Questionnaire (ACQ) Results

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