Please select the eligibility criteria that correspond to the clinical trial below.
Title: Effects of Macrolides on Asthma Control, Airway Inflammation and Bacterial Colonisation in Smokers With Asthma.
Brief Summary: Asthma is a common disease in Westernised societies, affecting up to 10% of the population. Corticosteroids are the most effective treatment for asthma but the therapeutic response varies considerably between individuals. A major cause of corticosteroid insensitivity in asthma is cigarette smoking. Active cigarette smoking occurs in over 25% of adults with asthma and a further 25% are ex-smokers. In a series of proof of concept clinical studies the investigators demonstrated for the first time that the efficacy of inhaled and oral corticosteroids is markedly impaired in smokers with asthma and to a lesser extent in ex-smokers with asthma. Active cigarette smoking has other detrimental effects on asthma morbidity including more severe symptoms, increased rates of hospitalisation, and accelerated decline in lung function. Smoking cessation advice is often ineffective because many adult smokers with asthma do not believe that they are personally at risk from their smoking, take many years until stopping smoking and frequently restart smoking after quitting. Alternative or additional drugs to corticosteroids are needed for smokers with asthma who are unable to obtain the clinical benefits associated with stopping smoking. In a proof of concept clinical trial the investigators will test the hypothesis that macrolides improve asthma control and reduce sputum neutrophil counts of smokers with chronic asthma.


Options:
A: Inclusion criteria

Patients meeting all of the following criteria will be considered for admission to the study:

* Adults, either sex, ages 18-55 years or age 56 to 65 with \< 20 pack year smoking history or \>65 with \<5 pack year smoking history
* Patients with a documented history of asthma for \>6 consecutive months, and
* Patients presenting within 48 hours (of initial presentation to medical care) with an acute deterioration in asthma control (increased wheeze, dyspnea and/or cough and/or reduced PEF) and requiring a course of oral steroids
* Patients with a PEF or FEV1 less than 80% of predicted normal or patient's best at presentation, at recruitment or in the time elapsed between presentation and recruitment
* Patients must be able to complete diaries and quality of life questionnaires.
* Patients must sign and date an informed consent prior to any study procedures.

Exclusion criteria

Patients presenting with any of the following will not be included in the study:

* Patients with known prolongation of the QT interval, a history of torsades de pointes, congenital long QT syndrome, bradyarrhythmias or uncompensated heart failure, patients on drugs known to prolong the QT interval and patients with ongoing proarrhythmic conditions such as uncorrected hypokalemia or hypomagnesemia, clinically significant bradycardia, and patients receiving Class IA (quinidine, procainamide) or Class III (dofetilide, aminodarone, sotalol) antiarrhythmic agents.
* Smokers aged 56-65 with a \>20 pack year history, or aged \>65 with \>5 pack year history
* Patients requiring immediate placement in ICU
* Patients who used oral or systemic antibiotics within 28 days prior to enrolment
* Patients with known impaired hepatic function (ALT/AST \> 2 ULN)
* Patients with significant lung disease (including COPD) other than asthma
* Patients with \> 20mg oral corticosteroid maintenance therapy
* Patients requiring other antibiotic therapy
* Patients who are receiving other medications or who have other disease conditions or infections that could interfere with the evaluation of drug efficacy or safety
* Women who are breast-feeding or are pregnant, as demonstrated by a urine pregnancy test carried out before exposure to study medication or the start of any study procedure that could pose a risk to the foetus
* Patients with suspected or known hypersensitivity to, or suspected serious adverse reaction to Azithromycin or any of the macrolide or ketolide class of antibiotics, erythromycin or to any excipients thereof
* Patients who have received treatment with any other investigational drug within 1 month prior to study entry, or have such treatment planned for the study period during treatment and follow up phase
* Patients with a concomitant condition (including clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic disease) making implementation of the protocol or interpretation of the study results difficult
* Patients with mental conditions rendering them unable to understand the nature, scope, and possible consequences of the study.
* Patients unlikely to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits.
* No subject will be allowed to enrol in this study more than once.
B: Inclusion Criteria:

* Participation in the COPSAC2010 cohort
* recurrent wheeze
* and others

Exclusion Criteria:

* Macrolide allergy
* Heart, liver or kidney disease.
* and others
C: Inclusion Criteria:

* Diagnosis of asthma
* Age 18-70
* Current smoker
* Duration of symptoms \>1yr with stability for 4 weeks
* Able to maintain asthma without exacerbations during run in period
* Able to wean off other asthma medication

Exclusion Criteria:

* Ex-smokers or never smokers
* Planning to quit smoking during duration of trial
* Patients with unstable asthma
* Patients with current epilepsy, psychosis or history of significant atrial or ventricular tachyarrhythmia
* Corrected QT-interval greater than 450msec in women, 430msec in men
* Low potassium levels. If can be corrected then screening can continue with confirmation of normal levels prior to taking study medication
* Liver disease (ALT and/or AST levels 2 or more times ULN)
* Significant renal disease (Creatinine or urea levels 2 or more times ULN)
* Any previous severe adverse reactions to macrolides
* Patients who are known to have specific IgE sensitivity or skin test positivity to grass pollen and a history of worsening of asthma due to hay fever will not be recruited from mid May to the end of July
* Upper or lower respiratory tract infection in the 4 weeks prior to randomisation. Run in period can be prolonged in this situation to have 4 weeks with no respiratory infection prior to randomisation.
* Patients who require medications known to interact with azithromycin
* On other immunosuppressants or chronic antibiotics
* Weight less than 45kg
* Frequent asthma exacerbations (greater than 4) requiring oral corticosteroids in the year prior to randomisation
* Current or past diagnosis of allergic-bronchopulmonary-aspergillosis
* Pregnancy and breast feeding
* Mental impairment or language difficulties that makes informed consent not possible
D: Inclusion criteria

Patients meeting all of the following criteria will be considered for enrollment in the study:

* A documented history of asthma for \>6 months
* Presenting within 24 hours of initial medical care in an urgent care clinic, emergency room, or in-patient hospital setting. To qualify for enrollment they must present with the following signs and symptoms of an acute deterioration in asthma control: (reduced PEFR, increased wheeze, and dyspnea, with or without cough).
* A PEFR less than 80% of predicted normal
* Females who meet the following conditions:

  * postmenopausal for at least 1 year, or
  * surgically incapable of bearing children, or
  * of childbearing potential, and all of the following conditions are met:

    * had a normal menstrual flow within 1 month before study entry and
    * has a negative pregnancy test (serum b-subunit human chorionic gonadotropin \[hCG\]) immediately before study entry and
    * must agree to abstinence or use of an accepted method of contraception

Exclusion criteria

Patients presenting with any of the following will not be included in the study:

* Requiring immediate placement in an Intensive Care Unit
* Obvious known allergic precipitant for this episode of acute severe asthma (e.g., acute exposure to animal dander)
* Pneumonia
* Known long QT syndrome or familial history of long QT syndrome (if no previous electrocardiogram \[ECG\] has invalidated this risk factor), or personal history of coronary disease, ventricular arrhythmia, bradycardia \<50 beats/min, or known uncorrected hypokalemia or magnesemia
* Known impaired hepatic or renal function
* Known diagnosis of myasthenia gravis
* Active or quiescent tuberculosis infections of the respiratory tract
* Acute exacerbation of chronic bronchitis, chronic obstructive pulmonary disease, cystic fibrosis, or emphysema
* A history of smoking of 10 pack-years or more
* Women who are breast feeding or are pregnant, as demonstrated by serum or urine pregnancy tests
* Suspected or known hypersensitivity to, or suspected serious adverse reaction to the macrolide class of antibiotics
* A concomitant condition (including clinically relevant cardiovascular, hepatic, neurologic, endocrine, or other major systemic disease) that would make implementation of the protocol or interpretation of the study results difficult
* A recent (within the previous 3 months) history of alcohol or recreational drug misuse.
* Immunocompromised patients, including but not limited to:

  * patients with known human immunodeficiency virus (HIV) infection and have either had or have an AIDS defining condition (e.g., Kaposi's sarcoma, Pneumocystis carinii pneumonia) or a CD4 + T lymphocyte count of \<200/mL
  * patients with neutropenia (\<1500 neutrophils/mm3)
  * patients with metastatic or hematological malignancy
  * splenectomized patients or patients with known hyposplenia or asplenia
* Planned surgical treatment at any time during the course of the study that would be incompatible with the objectives of this study
* Other disease conditions or infections that could interfere with the evaluation of study treatment efficacy or safety
* Oral steroid-dependent asthma
* Antibiotic use within 30 days prior to enrollment
* Treated within 2 weeks prior to inclusion with CYP3A4 inducers such as rifampicin, phenytoin, carbamazepine, and St. John's Wart
* Currently receiving medication known to prolong QT interval such as cisapride, pimozide, astemizole and terfenadine, or potent CYP3A4 inhibitors such as antiproteases or ketoconazole.
* Patients in whom an antibiotic is clearly indicated.
* Have received treatment with any other investigational drug within 1 month prior to study entry, or have such treatment planned for the study period during treatment and follow-up phase

Answer: C