| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
| E.1.2 | System Organ Class | 10038738 - Respiratory, thoracic and mediastinal disorders |
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| 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 Fp MDPI and FS MDPI when administered over 12 weeks in patients 4 through 11 years of age with persistent asthma. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of this study is to evaluate the safety and tolerability of Fp MDPI and FS MDPI. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
a. The patient is a male or female patient 4 through 11 years of age, inclusive, when informed consent/assent (as applicable) is signed.
b. Written informed consent must be signed and dated by parent/legal guardian and the written informed assent form must be signed and dated by the patient (as applicable, per local regulations) before any study-related procedures are conducted.
c. The patient has a diagnosis of asthma as defined by the NIH. The asthma diagnosis has been present for a minimum of 3 months before SV.
d. The patient has persistent asthma with a FEV1 ≥50% and ≤90% of the value predicted for age, height, sex, and race at the SV as measured by handheld device.
e. The patient’s persistent asthma is stable and is currently being treated with stable asthma therapy for at least 30 days before the SV. Patients who are currently on SABA regimen only or PRN only are not eligible for the study.
f. The patient has demonstrated ≥10% response to a bronchodilator from screening FEV1 within 30 minutes after 2 to 4 inhalations of albuterol/salbutamol HFA MDI (90 mcg ex-actuator) or equivalent at SV as measured by handheld device. Patients who demonstrated <10% response to a bronchodilator may retest within 7 days of their initial SV.
Patients who demonstrate response to a bronchodilator ≥10% and <14.50% may enter the run-in period (provided that they meet the other inclusion and none of the exclusion criteria) and may present for repeat lung function assessments by handheld device and another bronchodilator test within 14±2 days, during which they must demonstrate at least a 15% response to a bronchodilator. If the criteria are not met, patients may continue in the run-in period for up to 14 additional days to meet the lung function assessment and response to bronchodilator criteria (1 final attempt) for randomization. Patients may only continue in the run-in period if the investigator determines, by assessing the patient’s asthma status (at each investigational center visit), that it is safe for the patient to continue.
g. The patient (with assistance from parents/legal guardians/caregivers, as needed) is able to perform technically acceptable lung function assessments by handheld device. Patients who fail to demonstrate technically acceptable lung function assessments may retest within 7 days of their initial SV.
h. The patient (with assistance from parents/legal guardians/caregivers, as needed) is able to use an MDI device and an MDPI device.
i. The patient is able to withhold (as judged by the investigator) his/her rescue medication for at least 6 hours before SV and all TVs where lung function assessments are performed.
j. The patient is assessed as otherwise healthy, with clinically acceptable medical history, physical examination, and vital signs within acceptable ranges for children with asthma as assessed by the investigator.
k. All patients must be able to replace their current SABA with albuterol/salbutamol HFA MDI inhalation aerosol at the SV for use as needed for the duration of the study.
l. Female patients who have reached puberty and achieved menarche (as determined by the investigator) must be counseled regarding the possible unknown risks associated with IMP during pregnancy following permission of the parents/legal guardians. A urine pregnancy test must be negative for these patients at SV. Eligible female patients who are known to be sexually active will be excluded.
m. Eligible male patients who are known to be sexually active will be excluded. |
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| E.4 | Principal exclusion criteria |
a. The patient has a history of life-threatening asthma exacerbation (asthma episode that required intubation and/or was associated with hypercapnia, respiratory arrest, or hypoxic seizures).
b. The patient is pregnant or lactating or plans to become pregnant during the study period or within 30 days after the patient’s last study-related visit.
c. The patient has participated as a randomized patient in any investigational drug study within the 30 days or within 5 half-lives preceding the SV (or prescreening visit) or plans to participate in another investigational drug study at any time during this study.
d. The patient has a known hypersensitivity to any corticosteroid, salmeterol, or any of the excipients in the IMP or rescue medication formulation. Dietary lactose intolerance does not exclude from inclusion or as per the investigator’s medical discretion.
e. The patient has been treated with any known strong cytochrome P450 (CYP) 3A4 inhibitors within 30 days before the SV or plans to be treated with any strong CYP3A4 inhibitor during the study.
f. The patient has been treated with any of the prohibited medications during the prescribed washout periods before the SV.
g. The patient currently smokes or has a smoking history. The patient must not have used tobacco products within the past year.
h. 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 the SV (note: patients who develop a URI or LRI during the run-in period may be rescreened 2 weeks after symptoms resolve).
i. The patient has had an asthma exacerbation requiring systemic corticosteroids within 30 days before the SV or has had any hospitalization for asthma within 2 months before the SV.
j. 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 SV and have been on a stable (maintenance) dose for 30 days or more before the SV may be considered for inclusion.
k. The patient has used immunosuppressive medications within 30 days before the SV.
l. The patient is unable to tolerate or unwilling to comply with the appropriate washout periods and withholding of all applicable medications.
m. The patient has untreated oral candidiasis at the SV. Patients with clinical visual evidence of oral candidiasis who agree to receive treatment and comply with appropriate medical monitoring may enter the run-in period.
n. The patient has a history of a positive test for HIV, active hepatitis B virus, or hepatitis C infection.
o. The patient is an immediate relative of an employee of the clinical investigational center.
p. A member of the patient’s household is participating in the study at the same time. However, after the enrolled patient completes or discontinues participation in the study, another patient from the same household may be screened.
q. The patient has a disease/condition that, in the medical judgment of the investigator, would put the safety of the patient at risk or that could affect the efficacy or safety analysis if the disease/condition worsened during the study. Examples include/ not limited to:
-cardiovascular conditions including clinically significant cardiac arrhythmia, known aortic aneurysm, congenital heart disease, coronary heart disease, or vital signs clinically unacceptable for ranges in children with asthma as assessed by the investigator
-hepatic, renal, hematologic, neuropsychologic, or endocrine conditions (eg, sickle cell disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, Addison’s disease, Cushing’s syndrome, stroke within 3 months before the SV)
-gastrointestinal conditions (eg, poorly controlled peptic ulcer, poorly controlled gastroesophageal reflux)
-infectious/immunologic conditions including untreated tuberculosis (a history of tuberculosis is acceptable only if a patient has received an approved prophylactic treatment regimen or an approved active treatment regimen and has had no evidence of active disease for a minimum of 2 years) and immunologic compromise
-ocular conditions including glaucoma, ocular herpes simplex, or cataracts
-oncologic conditions including any current malignancy, excluding basal cell carcinoma. History of malignancy is acceptable only if the patient has been in remission for 1 year before the SV. Remission is defined as no current evidence of malignancy and no treatment for the malignancy in the 12 months before the SV.
-pulmonary conditions including chronic bronchitis, emphysema, chronic bronchiectasis, cystic fibrosis, chronic lung disease, or chronic obstructive pulmonary disease -renal conditions including chronic renal failure or ongoing dialysis
-history of or planned solid organ transplant
r. Vulnerable patients (ie, people kept in detention) are excluded from participation.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
-For Fp MDPI versus placebo: the change from baseline in weekly average of the percent predicted trough morning FEV1 at week 12
-For FS MDPI versus Fp MDPI: the change from baseline in 1-hour postdose percent predicted morning FEV1 at week 12 |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The baseline percent predicted FEV1 will be the weekly average of the morning FEV1 prior to the first IMP dose. The first day before randomization consists of the entry on the morning of the RV in the patient diary built into the handheld device. The weekly average of the percent predicted FEV1 at week 12 will be the average values based on the available data at that week.
For the endpoint of change from baseline in 1-hour postdose percent predicted morning FEV1 (measured at the clinic) at week 12, baseline is defined as predose FEV1 measurements obtained at the clinic at the RV with the handheld device immediately prior to the IMP administration.
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| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoints:
-Change from baseline in the weekly average of daily trough morning (predose and pre-rescue bronchodilator) PEF over 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 through 12
-Change from baseline in the weekly average of the total daily asthma symptom score (defined as the average of the daytime and nighttime scores) over weeks 1 through 12
-Change from baseline in asthma control (measured by Childhood Asthma Control Test [C-ACT]) over the 12-week treatment period
-Time to first onset of effect defined as the first decrease from baseline in daily rescue medication use
-Proportion of patients discontinued from IMP for asthma exacerbation during the 12-week treatment period
Safety endpoints:
-Incidence of adverse events throughout the study
-Vital signs assessments throughout the study
-Oropharyngeal examination findings at each visit
-Physical examination findings at baseline and at week 12 or at the IMP discontinuation visit (IMPDV) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Secondary efficacy endpoints:
Recorded in patient diary daily throughout 12 week study treatment period: during the treatment period (RV through TV6 [week 12] or IMPDV), daily in the morning and evening at approximately the same time each day, patients will use the handheld device at home to record asthma symptom scores and rescue albuterol/salbutamol HFA MDI use, after which they will perform lung function assessments (FEV1 and PEF) and then will take their dose of the IMP and record IMP dosing in the patient diary built into the handheld device.
Safety measures and time points are as follows:
-inquiries about adverse events at all visits
-vital signs measurements at all visits
-oropharyngeal examinations at all visits
-physical examinations at baseline and week 12 or at the IMPDV
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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 | Yes |
| 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) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 10 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| 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 |
| Georgia |
| Hungary |
| Poland |
| Russian Federation |
| Ukraine |
| 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 | 1 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 15 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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