| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Respiratory Tract Diseases [C08] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of this study is to evaluate the efficacy of beclomethasone dipropionate (320 or 640 mcg/day) administered via BAI and MDI with placebo treatment in patients with persistent asthma as assessed by the change from baseline in trough morning forced expiratory volume in 1 second (FEV1) over the 12 week treatment period. |
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| E.2.2 | Secondary objectives of the trial |
To evaluate the efficacy of beclomethasone dipropionate treatment administered via BAI and MDI compared with placebo treatment in patients with persistent asthma as assessed by the change from baseline in weekly average of daily trough morning and evening peak expiratory flow (PEF), in the time to patient withdrawal due to meeting stopping criteria for worsening asthma, in change from baseline in rescue medication use, and the change from baseline in the weekly average of the total daily asthma symptom score during the 12 week treatment period
To evaluate the safety and tolerability of beclomethasone dipropionate treatment as assessed by the occurrence of treatment emergent adverse events (TEAEs) and vital signs assessments throughout the study; physical examination findings and clinical laboratory evaluations at SV and the final treatment visit (TV4/TdV); and oropharyngeal examination findings at every visit. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. Severity of disease: The patient has persistent asthma, with an FEV1 40% 85% of the value predicted for age, height, sex, and race as per the National Health and Nutrition Examination Survey (NHANES III) reference values at the screening visit (SV).
b. Current asthma therapy: The patient must be on a stable dose of an inhaled corticosteroid (ICS) of at least 440 mcg/day of fluticasone propionate or equivalent for a minimum of 4 weeks before SV, or any ICS/long acting β2 agonist (LABA) combination for a minimum of 4 weeks before the prescreening visit.
c. Reversibility of disease: The patient has demonstrated at least 12% reversibility and 200 mL increase from baseline FEV1 (patients age 18 and older) within 30 minutes after 2 4 inhalations of albuterol/salbutamol hydrofluoroalkane (HFA) MDI (90 mcg ex actuator) or equivalent at SV. Reversibility values of 11.50 11.99 will be rounded to 12. A documented historical reversibility, including flow loops, of at least 12% and 200 mL increase from baseline FEV1 (patients age 18 and older) to a beta agonist in the previous 12 months before SV is also acceptable. Note: Patients who do not qualify for the study due to either failure to meet baseline spirometry, failure to meet reversibility, or failure to achieve spirometry consistent with American Thoracic Society/European Respiratory Society (ATS/ERS) criteria will be permitted to perform a retest once within 7 days or will be permitted to rescreen once at least 7 days after the date of screening.
d. Written informed consent/assent is obtained. For adult patients (age 18 and older, or as applicable per local regulations), the written informed consent form must be signed and dated by the patient before conducting any study related procedure. For minor patients (ages 12 to 17 years, or as applicable per local regulations), the written informed consent form must be signed and dated by the parent/legal guardian and the written informed assent form must be signed and dated by the patient before conducting any study related procedure.
e. The patient is a male or female 12 years of age or older as of the visit when informed consent/assent is signed (screening or prescreening visit, as applicable).
f. Asthma diagnosis: The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis has been present for a minimum of 3 months and has been stable (defined as no exacerbations and no changes in medication) for at least 30 days.
g. The patient is able to perform acceptable and repeatable spirometry consistent with the ATS/ERS 2005 criteria.
h. The patient is able to perform PEF with a hand held peak flow meter.
i. The patient is able to use an MDI device without a spacer device and a BAI device.
j. The patient is able to withhold (as judged by the investigator) his or her regimen of ICS or study drug, and rescue medication for at least 6 hours before SV and the treatment visits in which spirometry will be conducted (SV, randomization visit [RV], treatment visit [TV] 1, TV2, TV3, and TV4).
k. The patient/parent/guardian/caregiver is capable of understanding the requirements, risks, and benefits of study participation, and, as judged by the investigator, capable of giving informed consent/assent and being compliant with all study requirements.
l. If patient is a female, she is currently not pregnant, breast feeding, or attempting to become pregnant (for 30 days before SV and throughout the duration of the study and for 30 days after the patient's last visit), or is of non childbearing potential, as defined by any of the following:
-premenarche
-at least 1 year postmenopausal
-surgically sterile
-congenitally sterile
-diagnosed as infertile and not undergoing treatment to reverse infertility
OR, if of childbearing potential, has a negative serum pregnancy test and is willing to commit to using a consistent and acceptable method of birth control as defined below for the duration of the study:
-systemic contraception used for at least 1 month before screening, including birth control pills, transdermal patch, vaginal ring, levonorgestrel implant, or injectable progesterone
-double barrier method (condoms, cervical cap, diaphragm, and vaginal contraceptive film with spermicide)
-intrauterine device (IUD) with a low failure rate (defined as less than 1% per year)
-monogamous with a vasectomized male partner or exclusively has same sex partners
OR, if of childbearing potential, is not sexually active or has a negative serum pregnancy test, and is willing to commit to using a consistent and acceptable method of birth control as defined above for the duration of the study, in the event she becomes sexually active.
If male and sexually active, the patient is willing to commit to an acceptable method of birth control for the duration of the study or exclusively has same sex partners.
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| E.4 | Principal exclusion criteria |
a. The patient has a history of life threatening asthma, defined for this protocol as an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest, or hypoxic seizures.
b. The patient is pregnant or lactating, or plans to become pregnant or to donate gametes (ova or sperm) for in vitro fertilization during the study period or for 30 days after the patient’s last study related visit (for eligible patients only, if applicable). Eligible female patients unwilling to employ appropriate contraceptive measures to ensure that pregnancy will not occur during the study will be excluded. Any patient becoming pregnant during the study will be withdrawn from the study.
c. The patient has participated in any investigational drug study within the 30 days preceding SV (or prescreening visit, as applicable), or plans to participate in another investigational drug study at any time during this study.
d. The patient has previously participated in a beclomethasone dipropionate BAI study as a randomized patient.
e. The patient has a known hypersensitivity to any corticosteroid or any of the excipients in the study drug or rescue medication formulation.
f. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors (eg, azole antifungals, ritonavir, clarithromycin) within 30 days before SV or plans to be treated with any strong CYP3A4 inhibitor during the study.
g. The patient has been treated with any of the prohibited medications during the prescribed (per protocol) washout periods before SV.
h. The patient currently smokes or has a smoking history of 10 pack years or more (a pack year is defined as smoking 1 pack of cigarettes/day for 1 year). A patient may not have used tobacco products within the past year (eg, cigarettes, cigars, chewing tobacco, or pipe tobacco).
i. The patient has a culture documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus, or middle ear that has not resolved at least 2 weeks before SV.
j. The patient has a history of alcohol or drug abuse within 2 years preceding SV.
k. The patient has had an asthma exacerbation requiring oral corticosteroids within 1 month before SV, or has had any hospitalization for asthma within 2 months before SV
l. Initiation or dose escalation of immunotherapy (administered by any route) is planned during the study period. However, patients who initiated immunotherapy 90 days or more before the screening visit (SV) and have been on a stable (maintenance) dose for 30 days or more prior to SV may be considered for inclusion.
m. The patient has used immunosuppressive medications within 4 weeks before SV.
n. The patient is unable to tolerate or unwilling to comply with the required washout periods and withholding of all applicable medications.
o. The patient has untreated oral candidiasis at SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the study.
p. The patient has had a positive test for human immunodeficiency virus (HIV), active hepatitis B virus, or hepatitis C infection.
q. The patient is either an employee or an immediate relative of an employee of the clinical investigational center.
r. A member of the patient’s household is participating in the study at the same time.
s. The patient has historic or current evidence of a clinically significant disease, including but not limited to the following:
-cardiovascular conditions (eg, congestive heart failure, known aortic aneurysm, clinically significant cardiac arrhythmia, coronary artery disease)
-hepatic, renal, hematologic, neuropsychologic, or endocrine conditions (eg, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome)
-gastrointestinal conditions (eg, poorly controlled peptic ulcer disease, gastroesophageal reflux disease)
-pulmonary conditions (eg, bronchiectasis with the need for treatment, cystic fibrosis, bronchopulmonary dysplasia)
Note: Chronic obstructive pulmonary disease/chronic bronchitis is expressly prohibited.
-current malignancy, excluding basal cell carcinoma
-current or untreated tuberculosis
-uncontrolled hypertension (systolic blood pressure of at least 160 mm Hg or diastolic blood pressure over 100 mm Hg)
-stroke within 3 months before SV
-immunologic compromise
-ocular disturbances, including glaucoma, cataract, or herpes simplex infection
-Significant disease is defined as any disease that in the medical judgment of the investigator would put the safety of the patient at risk through participation or that could affect the efficacy or safety analysis if the disease/condition worsened during the study. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable for this study is the change from baseline in trough morning (pre dose and pre rescue bronchodilator) FEV1 over the 12 week treatment period. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Primary efficacy endpoint timeline is over the 12-week treatment period. |
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| E.5.2 | Secondary end point(s) |
The secondary endpoints include:
• Change from baseline in weekly average of daily trough morning (pre dose and pre rescue bronchodilator) PEF over the 12 week treatment period
• Change from baseline in weekly average of daily evening PEF over the 12 week treatment period
• Time to patient withdrawal due to meeting stopping criteria for worsening asthma during the 12 week treatment period
• Change from baseline in the weekly average of total daily (24 hour) use of albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 1-12
• Change from baseline in the weekly average of the total daily asthma symptom score (the total daily asthma symptom score is the average of the daytime and nighttime scores) over weeks 1-12
• Change from baseline in the percentage of rescue free days (defined as 24 hour periods with no rescue medication usage) during the 12 week treatment period |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline in weekly average of daily trough morning (pre dose and pre rescue bronchodilator) PEF over the 12 week treatment period
• Change from baseline in weekly average of daily evening PEF over the 12 week treatment period
• Time to patient withdrawal due to meeting stopping criteria for worsening asthma during the 12 week treatment period
• Change from baseline in the weekly average of total daily (24 hour) use of albuterol/salbutamol inhalation aerosol (number of inhalations) over weeks 1-12
• Change from baseline in the weekly average of the total daily asthma symptom score over weeks 1-12
• Change from baseline in the percentage of rescue free days during the 12 week treatment period |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 52 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Bulgaria |
| Germany |
| Hungary |
| Poland |
| United States |
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| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 5 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
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