| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 |
|
| 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. |
|
| 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. |
|
| 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. |
|
| 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).
|
|
| 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). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Within the 6 months post-randomization. |
|
| 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. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Entire treatment period (up to 6 months). |
|
| 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 |
|
| 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
|
| Last post-treatment follow up phone contact last subject |
|
| 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 | 7 |
| 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 |
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