| 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 the study is to demonstrate the efficacy of Symbicort pMDI 80/4.5 μg, 2 actuations twice daily, and Symbicort pMDI 80/2.25 μg, 2 actuations twice daily, compared with budesonide pMDI 80 μg, 2 actuations twice daily, in children ages 6 to <12 years with asthma. |
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| E.2.2 | Secondary objectives of the trial |
| The secondary objective of the study is to compare the efficacy of Symbicort pMDI 80/4.5 μg, 2 actuations twice daily, with Symbicort pMDI 80/2.25 μg, 2 actuations twice daily, in children ages 6 to <12 years with asthma. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
For inclusion in the study, patients should fulfill the following criteria at Visit 1:
1. Provision of a signed and dated (by the parent or legal guardian) written Informed Consent form (and assent form, per Institutional Review Board [IRB]/Ethics Committee [EC] requirements) prior to undergoing any study-related procedures including being asked to withdraw regularly used medications
2. Be between the ages of 6 and <12 years (not having reached his/her 12th birthday at the time of Visit 1)
3. Have a documented clinical diagnosis of asthma as defined by the ATS (ie, a disease characterized by increased responsiveness of the trachea and bronchi to various stimuli and manifested by widespread narrowing of the airway that changes in severity either spontaneously or as a result of therapy) for at least 6 months prior to Visit 2.
4. If receiving immunotherapy injections, a patient must have been on a stable maintenance regimen for at least 6 weeks and be expected to remain on immunotherapy throughout the study.
5. Require and be prescribed treatment with a consistent daily dose of ICS within the corresponding dosage range listed below for at least 4 weeks prior to Visit 1. If the patient is not under the care of the investigator, documentation of ICS use by pharmacy records or copies of the prescribing health care provider’s records are required to verify ICS use.
- Budesonide 320 μg to 540 μg/day
- Beclomethasone HFA: 160 to 320 μg/day
- Budesonide (nebulized): 1000 μg/day
- Flunisolide: 1000 to 1250 μg/day
- Flunisolide HFA: 320 μg/day
- Flunisolide HFA pMDI: 176 to 352 μg/day
- Fluticasone DPI: 200 to 400 μg/day
- Triamcinolone acetonide: 600 to 900 μg/day
- Ciclesonide: 160 to 320 μg/day
- Mometasone: 110 to 220 μg/day
- OR on a fixed combination of ICS and LABA
Note: Other non-steroidal asthma medications (eg, leukotriene modifiers, mast cell stabilizers) could have been used in combination with any of the above and would not impact a patient’s eligibility. These medications must be discontinued at or before Visit 2. After providing written informed consent for the study, potential patients maintained on a fixed combination of ICS and LABA should be switched
to a comparable dose of ICS without the addition of LABA at least 48 hours prior to Visit 2. This change will not be considered a change in the dose of maintenance ICS.
For inclusion in the study, patients should fulfill the following criteria at Visit 2:
6. Have a morning pre-bronchodilator clinic FEV1 measured at least 6 hours after the last dose of inhaled SABA and at least 48 hours after the last dose of inhaled LABA of 60% to 100% of predicted normal. Polgar predicted normal standards will be used for all patients. Race correction will be applied as appropriate. If the patient is
taking a fixed combination of ICS/LABA, the patient is to be placed on a comparable dose of ICS monotherapy, without LABA, at least 48 hours prior to Visit 2.
7. Demonstrate reversibility of clinic FEV1 of ≥12% from pre- albuterol/salbutamol level within 15 to 30 minutes after administration of a standard dose of albuterol/salbutamol (albuterol/salbutamol pMDI, 90/100 μg per inhalation, 2 to 4 actuations, with or without a spacer, or up to 2.5 mg of nebulized
albuterol/salbutamol). For patients who fail to demonstrate reversibility at Visit 2, but meet all of the other inclusion criteria and none of the exclusion criteria, the assessment can be repeated once, after Visit 2, but prior to Visit 3.
8. Demonstrated ability to use any device to be used in the study |
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| E.4 | Principal exclusion criteria |
1. Have been hospitalized at least once or required emergency treatment more than once for an asthma-related condition during the 6 months prior to Visit 1
2. Have required treatment with systemic corticosteroids (eg, oral, parenteral, or rectal) for any reason within the 6 weeks prior to Visit 1
3. Have any significant disease or disorder (eg, cardiovascular, pulmonary [other than asthma], gastrointestinal, hepatic, renal, neurological, musculoskeletal, endocrine, metabolic, malignant, psychiatric, major physical impairment) or other disease or
condition generally affecting lung function (eg, prematurity, congenital lung anomalies, tracheoesophageal fistula, bronchiectasis, chronic sinusitis) which, in the opinion of the investigator, could place the patient at risk if participating in the study, or could influence the results of the study or the patient's ability to participate in the study
4. Have participated in another investigational drug study during the 4 weeks prior to Visit 1
5. Receiving treatment withβ-blocker (including eye drops)
6. Have taken omalizumab (Xolair®, Genentech/Novartis) or any other monoclonal or polyclonal antibody therapy, for any reason within the 6 months prior to Visit 2
7. Have a known or suspected hypersensitivity to albuterol/salbutamol, or budesonide, or formoterol, and/or their excipients and/or have a severe hypersensitivity to milk proteins
8. Have any clinically relevant abnormal findings in physical examination or vital signs at Visit 2, which, in the opinion of the investigator, may put the patient at risk because of his/her participation in the study
9. Have a planned hospitalization at any time during the study
10. Have a positive pregnancy test at any time during study |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy variable to be analyzed to address the primary and secondary objectives will be the 1-hour post-dose forced expiratory volume in the first second (FEV1) (L) measured in clinic (clinic FEV1). |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
The secondary efficacy variables to be analyzed to address the primary and secondary objectives will be:
* Pre-dose clinic FEV1 (L), clinic FVC (L), clinic FEF25-75 (L/s), and clinic PEF
(L/min)
* Fifteen-minute post-dose clinic FEV1 (L), clinic FVC (L), clinic FEF25-75 (L/s), and clinic PEF (L/min)
* One-hour post-dose forced vital capacity (FVC) (L) measured in the clinic (clinic FVC)
* One-hour post-dose forced expiratory flow between 25% and 75% of the forced vital capacity (FEF25-75) (L/s) measured in the clinic (clinic FEF25-75)
* One-hour post-dose peak expiratory flow (PEF) (L/min) measured in the clinic (clinic PEF)
* Morning and evening FEV1 (L) and PEF (L/min) recorded in the electronic diary (eDiary)
* Nighttime, daytime, and total daily asthma symptom scores recorded in the eDiary
* Nighttime awakenings due to asthma symptoms requiring reliever use recorded in the eDiary during the single-blind run-in and the double-blind treatment periods
* Daytime, nighttime, and total daily reliever medication use recorded in the eDiary
* Paediatric Asthma Quality of Life Questionnaire with Standardised Activities (PAQLQ[S]) scores (overall and each domain)
* Time to occurrence of first asthma exacerbation
* Time to discontinuation of investigational product (IP) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 3 |
| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.5.1 | Number of sites anticipated in the EEA | 7 |
| 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 |
| Mexico |
| Panama |
| Slovakia |
| 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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| The end of the study is defined as "the last visit of the last patient undergoing the study". |
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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 | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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