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 | 14.1 |
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 is to evaluate whether the addition of a LABA to an ICS (FSC) therapy is non-inferior in terms of risk of serious asthma-related events (asthma-related hospitalizations, endotracheal intubations, and deaths) compared with ICS alone (FP) in pediatric subjects (age 4-11 years) with persistent asthma. |
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E.2.2 | Secondary objectives of the trial |
A secondary objective of the study is to evaluate whether the addition of LABA to ICS therapy (FSC) is superior to ICS therapy alone (FP) in terms of measures of efficacy in pediatric subjects (age 4-11 years) with persistent asthma. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
French subjects: In France, a subject will be eligible for inclusion in this study only if either affiliated to or a beneficiary of a social security category.
1. Informed consent
• Subject’s legal guardian must be able and willing to give written informed consent to take part in the study.
If applicable, subject must be able and willing to give assent to take part in the study according to the local requirement.
• Subject and their legal guardian understand that the study requires them to be treated on an outpatient basis.
• Subject and their legal guardian understand that they must comply with study medication and study assessments including recording of symptom scores and rescue albuterol/salbutamol use, attending scheduled study visits, and being accessible by a telephone call.
2. Age: 4-11 years of age at Visit 1
3. Gender: Male or eligible female. Female subjects should not be enrolled if they are pregnant, lactating or plan to become pregnant during the time of study participation. All females of childbearing potential must have a negative urine pregnancy test result prior to randomization to continue in the study. Females who become pregnant during the course of the study will be discontinued and the pregnancy outcome followed
4. Asthma diagnosis: Asthma, defined by the regional asthma guidelines (i.e., NIH, GINA, etc.), for at least 6 months prior to Visit 1.
Asthma is defined as a chronic inflammatory disorder associated with airway hyperresponsiveness and reversible airways obstruction that leads to recurrent episodes of wheezing, breathlessness, chest tightness, and coughing.
If the subject is naïve to the study site, the subject/guardian must self-report a physician diagnosis of asthma and the investigator must confirm by review of medical history with the subject/guardian.
5. Ability to answer questions regarding asthma control (with assistance of his/her parents [guardians], if needed), and use a metered-dose inhaler (MDI) and DISKUS effectively.
6. In countries where the product label includes a warning regarding more serious chickenpox infections in patients using corticosteroids (refer to the local product labels for varicella vaccine, ADVAIR DISKUS, and FLOVENT DISKUS) and/or varicella immunization is recommended for the age group, the subject must have a history of clinical varicella infection or recipient of a varicella vaccine before receiving any study drug. In those countries, subjects without a history of clinical varicella disease must receive varicella vaccine prior to randomization, and should follow standard guidelines regarding timing of second dose, if indicated.
7. Subject must have history of at least one occurrence (self-report by subject/guardian) of treatment with systemic corticosteroid [3 or more days of oral corticosteroid (OCS) or an equivalent depot corticosteroid injection] for an asthma exacerbation within the prior 12 months, excluding the 4 weeks immediately preceding Visit 1.
8. Currently being treated for asthma and no change in asthma therapy for the last 4 weeks from Visit 1 and Subjects must meet one of the following pre-study asthma medication, impairment domain (Childhood Asthma Control Test) and risk domain (asthma exacerbations) criteria to be eligible for enrolment.
• Subjects on SABA alone, LTRA, theophylline, or cromolyn as monotherapy with Childhood Asthma Control Test score ≤19 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or
• Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score ≥20 at Visit 1 and have had 2 or more asthma exacerbations in the previous year, or
• Subjects on low-dose ICS monotherapy with Childhood Asthma Control Test score ≤19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score ≥20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on low-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score ≤19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score ≥20 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS monotherapy with Childhood Asthma Control Test score ≤19 at Visit 1 and have had at least 1 asthma exacerbation in the previous year, or
• Subjects on medium-dose ICS and one or more adjunctive therapy (LABA, LTRA, or theophylline) with Childhood Asthma Control Test score ≥20 at Visit 1 and have had only 1 asthma exacerbation in the previous year. |
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E.4 | Principal exclusion criteria |
1. History of life-threatening asthma: Defined for this protocol as an asthma episode that required intubation, hypercapnea requiring non-invasive ventilatory support, respiratory arrest, hypoxic seizures or asthma-related syncopal episode(s).
2. Unstable asthma at Visit 1.
3. Subjects who are currently receiving high-dose ICS or ICS/LABA therapy to treat asthma symptoms.
4. Concurrent respiratory disease: Current evidence of pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, allergic bronchopulmonary aspergillosis, cystic fibrosis, bronchopulmonary dysplasia, or other severe respiratory abnormalities other than asthma.
5. Respiratory infection: Bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear (either culture-documented or suspected) that is not resolved at Visit 1 and that in the opinion of the investigator is expected to affect the subject’s asthma status or the subject’s ability to participate in the study.
6. Subjects with only exercise-induced asthma are excluded from participation in this study.
7. Asthma exacerbation: An asthma exacerbation requiring systemic (tablets, suspension or injection) corticosteroids within 4 weeks of Visit 1 or more than 4 separate exacerbations in the last 12 months from Visit 1.
These include asthma exacerbations resulting from poor compliance with asthma medications.
Each asthma exacerbation must be separated by >7 days from the discontinuation of OCS to be considered an individual event.
8. Asthma hospitalization: Hospitalization for asthma within 4 weeks of Visit 1 or more than 2 hospitalizations (defined as overnight admission) for asthma in the last 12 months from Visit 1. Each hospitalization must be separated by >7 days to be considered an individual event (ED visits < 24 hours in duration are not considered hospitalizations).
9. Other current evidence of clinically significant uncontrolled diseases/conditions of any body or organ system. Significant is defined as any disease/condition that, in the opinion of the investigator, would put the safety of the subject at risk through study participation, or which would confound the interpretation of the study results if the disease/condition exacerbated during the study.
10. Neurological or psychiatric disease or history of drug or alcohol abuse (of a subject or his/her guardian) which in the opinion of the investigator could interfere with the subject’s proper completion of the protocol requirements excludes study participation.
11. Investigational medications: A subject must not have participated in an interventional study or used any investigational drug for any disease state within 30 days prior to Visit 1.
12. Drug allergy: Any adverse reaction including immediate or delayed hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal, inhaled, or systemic corticosteroid therapy, or vehicle contained within these medications.
13. Severe hypersensitivity to cow’s milk proteins. Any immediate hypersensitivity reaction such as urticaria, angioedema, rash, or bronchospasm to milk proteins.
14. Concomitant medications: Administration of prescription or over the counter medications that would significantly affect the course of asthma, or interact with sympathomimetic amines such as: anti-IgE (omalizumab), anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic antidepressants, betaadrenergic blockers; phenothiazines, monoamine oxidase (MAO) inhibitors, or diuretics.
15. Potent cytochrome P450 3A4 (CYP3A4) inhibitors: A subject is not eligible if he/she is receiving potent CYP34A inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconzole).
16. Affiliation with investigator’s site: A subject will not be eligible for this study if he/she is an immediate family member of the participating investigator, subinvestigator, study coordinator, or employee of the participating investigator.
17. Children in Care: A Child in Care (CiC) is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible Institutional Review Board (IRB)/Independent Ethics Committee (IEC). |
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E.5 End points |
E.5.1 | Primary end point(s) |
The primary safety endpoint is the number of subjects experiencing the composite endpoint of serious asthma-related outcomes (asthma-related hospitalizations, endotracheal intubations, or deaths) over the 6-month study treatment period.
The primary efficacy endpoint is asthma exacerbations (defined as deterioration of asthma requiring the use of systemic corticosteroids for at least 3 days or a single depot corticosteroid injection). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Within the 6 months post-randomization. |
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E.5.2 | Secondary end point(s) |
Secondary safety endpoints are asthma-related hospitalizations, endotracheal intubations, and deaths, and withdrawals from study treatment due to asthma exacerbation.
Secondary efficacy endpoints are rescue-free days and asthma control days. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Entire treatment period (up to 6 months). |
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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 | Yes |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
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 | 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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 150 |
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 |
European Union |
Argentina |
Australia |
Brazil |
Canada |
Chile |
China |
Colombia |
Croatia |
Hong Kong |
India |
Japan |
Korea, Republic of |
Macedonia, the former Yugoslav Republic of |
New Zealand |
Peru |
Philippines |
Russian Federation |
Serbia |
South Africa |
Taiwan |
Thailand |
Ukraine |
United States |
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E.8.7 | Trial has a data monitoring committee | Yes |
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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Last post-treatment follow up phone contact last subject |
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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 | 3 |
E.8.9.1 | In the Member State concerned months | 10 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 10 |
E.8.9.2 | In all countries concerned by the trial days | 0 |