Asthma

The primary objective of the study is to demonstrate that the addition of FOM to FP therapy is non-inferior to FP therapy alone in terms of the risk of composite serious asthma-related events (asthma-related hospitalization, asthma-related intubation and asthma-related death).

Foradil®Aerolizer®

formoterol fumarate

12

Asthma exacerbations, albuterol (or equivalent drug) use,
symptom and rescue-free days, productivity (i.e., days of missed work/school, ability to perform normal daily activities), nighttime awakenings, ACQ-6 score, and unscheduled asthma-related resource utilization.

Inclusion criteria
Patients eligible for inclusion in this study must fulfill all of the following criteria:
1. Written informed consent, and assent if applicable, must be obtained before any assessment is performed.
2. Patients, and their legal representatives if applicable, must be willing to and capable of complying with all study procedures, study treatments, and study assessments, including ability to answer questions regarding asthma status and use a daily eDiary.
3. Male or female patients 12 years of age and older (age may be limited to ≥18 years depending on regulatory and/or ethics committee approval and/or country of participation).
4. Confirmed diagnosis of persistent asthma, as defined by national and international asthma guidelines (GINA; NIH; etc.) for at least 1 year prior to study enrollment. Investigators must use appropriate means to ensure and confirm the patient’s asthma diagnosis (e.g., patient history, pharmacy records, or chart records, etc.). If the patient is naïve to the study site, the diagnosis of asthma must be confirmed by patient history.
5. PEF>50% of predicted normal value. Percent predicted PEF values must be calculated using NHANES III with relevant equations that adjust for race and national origin (Hankinson 1999; Hankinson 2010).
6. Current and appropriate use of one of the following treatments for asthma:
 ICS or ICS with one or more adjunctive therapies (LABA, LTRA or theophylline) for at least 4 weeks prior to randomization (see Table 3-2 Asthma therapy recommended dose equivalents). Any patient maintained on a stable high dose ICS with or without one or more adjunctive therapies (LABA, LTRA or theophylline) must have an ACQ6 < 1.5 at Visit 1.  Leukotriene receptor antagonist (LTRA) (e.g., montelukast, zafirlukast, or pranlukast) or theophylline as monotherapy at a stable dose for at least 4 weeks prior to
randomization. Patients on LTRAs or theophylline are eligible only if they record an ACQ-6 score of  1.5 and in the Investigator’s clinical judgment, the patient’s asthma severity could justify treatment with ICS or ICS + LABA.  Daily albuterol (or equivalent drug) in the 4 weeks prior to randomization, but not more than 8 puffs a day on 2 consecutive days, or 25 puffs in one day, in the 7 days prior to randomization. Patients on daily albuterol (or equivalent drug) are eligible only if they record an ACQ-6 score of  1.5 and in the Investigator’s clinical judgment, the patient’s asthma severity could justify treatment with ICS or ICS + LABA.
7. Recent asthma exacerbation between 30 days and 12 months prior to randomization that either:  required treatment with systemic corticosteroids (tablets, suspension, or injection) or  required hospitalization (defined as an inpatient stay or > 24-hour stay in an
observation area in an emergency room or other equivalent facility).
Investigators must use appropriate means to ensure the accuracy of the patient’s exacerbation history (e.g., patient history, pharmacy records, hospital records, or chart records, etc.).
8. For women who are not postmenopausal (at least 12 months of non-therapy-induced amenorrhea) or surgically sterile (absence of ovaries and/or uterus): agreement to remain abstinent or use a highly effective method of contraception during the treatment period.
 Abstinence is only acceptable if it is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, or postovulation methods) and withdrawal are not acceptable methods of contraception.
 Examples of highly effective contraception include the following:
a. Combined oral contraceptive pill
b. Contraceptive transdermal patch
c. Intrauterine device
d. Implants for contraception
e. Injections for contraception (with prolonged release)
f. Hormonal vaginal device
g. Sterilization, surgical tubal ligation
h. Sole sexual partner consisting of surgically sterilized male partner with appropriate post-surgical verification of the absence of spermatozoa in the ejaculate
i. Double barrier methods: condom and occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository (Note: a female condom and male condom should not be used together as friction between the two can result in either product failing)

Exclusion criteria
Patients fulfilling any of the following criteria are not eligible for inclusion in this study:
1. History of life-threatening asthma episode that required intubation and/or was associated with hypercapnia requiring non-invasive ventilatory support.
2. Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other respiratory abnormalities other than asthma. Obstructive sleep apnoea is not an
exclusion criterion unless it is uncontrolled and has significant impact on respiratory system.
3. Current evidence of, or past physician assessment of, chronic bronchitis, emphysema, or chronic obstructive pulmonary disease.
4. History of smoking ≥10 pack years. Number of pack years is calculated as the (number of cigarettes per day/20) times number of years smoked.
5. Exercise induced asthma (as the only asthma-related diagnosis) not requiring daily asthma control medicine.
6. Suspected or documented bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved at randomization.
7. Worsening/unstable asthma within 7 days prior to randomization, defined as any one or
more of the following:
 Asthma symptoms that persisted throughout the day on 2 consecutive days;
 Nighttime awakening due to asthma ≥3 times;
 Albuterol (or equivalent drug) use for the acute worsening of asthma symptoms >8 puffs a day over 2 consecutive days or 25 puffs in one day;
 Asthma symptoms so severe that the patient was limited in their ability to perform
normal daily activity.
8. Any asthma exacerbation requiring systemic (tablets, suspension or injection)
corticosteroids within 30 days of randomization or more than 4 separate exacerbations in
the 12 months preceding randomization. For exacerbations to be considered separate
events there must be at least 7 days from the resolution of one exacerbation to the start of
the second exacerbation. Note: Investigators should use clinical judgment and consider
the patient's history of exacerbation, including the severity and interval since the last
exacerbation per current clinical guidelines, in determining whether a patient with
multiple exacerbations in the prior year should be enrolled in the study.
9. Two or more hospitalizations (defined as an inpatient stay or a >24 hour stay in
observation area in an emergency room or other equivalent facility) for treatment of
asthma in the 12 months preceding randomization. Each hospitalization must be separated
by >7 days to be considered an individual event.
10. Women who are pregnant, nursing (lactating), or plan to become pregnant during the time
of study participation. Pregnancy is defined as the state of a female after conception and
until the termination of gestation, confirmed by a positive serum hCG laboratory test.
11. Any known, pre-existing, clinically significant condition, disorder or disease of any body
or organ system that is uncontrolled with standard treatment and that, in the opinion of the
investigator, would put the safety of the patient at risk through study participation or
would confound the interpretation of the results if the condition, disorder or disease
exacerbated during the study.
12. Use of any investigational drug at the time of enrollment or within 30 days or 5 half-lives, whichever is longer.
13. Treatment with one or more dose of study medication in any of the other concurrent sponsored studies to investigate the safety of the addition of LABA to ICS.
14. History of hypersensitivity to any beta2-agonist, sympathomimetic drug, inhaled corticosteroids, or systemic corticosteroid therapy (regardless of route) or any component of the possible study treatments in this trial, including severe milk protein hypersensitivity.
15. Use of anti-IgE (e.g., omalizumab) or any other monoclonal antibody, in the 6 months prior to randomization.
16. Use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements that are likely to interfere with the study procedures or compromise patient safety within 7 days (or 14 days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the first dose of study medication.
17. Use of -blockers within one day prior to first dose of study medication.
18. Use of ICS, LABA, ICS+LABA, LTRAs, leukotriene modifiers, anticholinergics, or theophylline must be discontinued prior to the first dose of study medication.
19. Use of a potent CYP3A4 inhibitor within 4 weeks of randomization (e.g., ritonavir, atazanavir, clarithromycin, indinavir, itraconazole, nefazodone, nelfinavir, saquinavir, ketoconazole, telithromycin).
20. Patients who, in the opinion of the investigator, are not able and likely to be compliant with study treatments, properly use study drug devices (e.g. - DPI, MDI), or who have any disorder, situation, or diagnosis which could interfere with the proper completion of the
protocol requirements.
21. History of malignancy of any organ system (other than localized basal cell carcinoma of the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless of whether there is evidence of local recurrence or metastases.
22. Patients with past or current evidence of cardiac arrhythmias, especially third degree atrioventricular block, severe cardiac decompensation, idiopathic subvalvular aortic stenosis, severe hypertension, aneurysm, phaeochromocytoma, hypertrophic obstructive cardiomyopathy, thyrotoxicosis, or other severe cardiovascular disorders, such as tachyarrhythmias or severe heart failure. Patients with past or current evidence of ischaemic heart disease and cardiac arrhythmias are excluded unless they are not severe, clinically stable and are clinically under control with appropriate medications, as per medical judgement of the investigator.