| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Children aged 5-11 years with persistent uncontrolled asthma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Asthma: A medical condition where inflammation (redness and swelling) and constriction (tightening) of the airways is present in the lungs making it difficult to breath. |
|
| 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 | 17.0 |
| 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 |
|
| 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 the dose response, efficacy and safety of three doses of VI inhalation powder administered once daily in the evening in children aged 5-11 years with persistent uncontrolled asthma over a 4 week treatment period. |
|
| E.2.2 | Secondary objectives of the trial |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed Consent: Written informed consent from at least one parent/ legal guardian 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. The study investigator is accountable for determining a child's capacity to assent to participation in a research study, taking into consideration any standards set by the responsible IEC/IRB.
• 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 lephone call.
2. Age: 5-11 years at visit 1.
3. Gender: Male and pre-menarchial female. Pre-menarchial females are defined as any female who has yet to begin menses.
4. Diagnosis of asthma: Subjects must have a history of symptoms consistent with a diagnosis of asthma for at least 6 months prior to Visit 1.
5. Reversibility component for subjects able to perform acceptable pre and post bronchodilator FEV1 during the screening visit: Subjects must attempt lung function reversibility in FEV1 within 10-40 minutes following 2-4 inhalations of albuterol/salbutamol inhalation aerosol (or equivalent nebulized treatment with albuterol/salbutamol solution). No specific reversibility is required however the percent reversibility will be documented. Subjects unable to perform acceptable pre and post bronchodilator FEV can still be enrolled provided they meet all other subject selection criteria.
6. Asthma Severity: Subjects must have a pre-bronchodilator PEF between ≥50% to ≤90% of their best post-bronchodilator value (calculated from Visit 1 reversibility testing using spirometry generated PEF values).
7. Current asthma therapy: Subjects must be receiving stable asthma therapy (short acting beta-agonist (SABA) plus ICS (total daily dose FP 250mcg or equivalent) for at least 4 weeks prior to screening: (Please see table in study Protocol page 19)
8. Ability to use Dry Powder Inhalers: Subjects must demonstrate the ability to use the Novel Dry Powder Inhaler (NDPI) and the DISKUS/ACCUHALER under the supervision of their parents/carers.
9. Short-Acting Beta2-Agonists (SABA): All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1 for use as needed for the duration of the study. Subjects must be able to withhold albuterol/salbutamol for at least 6 hours prior to study visits. Albuterol/salbutamol MDI will be administered with or without a spacer to be used as determined by the investigator. The use or non-use of the spacer should be consistent for an individual subject throughout the study.
10. Peak Flow Meter/Daily Diary: A subject must be able to use the study-provided peak flow meter and the subject/caregiver must be able to maintain the electronic diary record. |
|
| E.4 | Principal exclusion criteria |
1. Life Threatening Asthma: Subjects with a 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. Asthma Exacerbation: Subjects with a history of asthma exacerbation requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or a depot corticosteroid injection (within 3 months) or requiring hospitalization for asthma (within 6 months) prior to screening.
3. Concomitant medications: Potent Cytochrome P450 3A4 (CYP3A4) inhibitors (e.g. Clarithromycin, atazanavir, indinavir, itraconazole, ketoconazole, nefazadone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine) (Please see table on page 21 of study protocol)
4. Infections: Culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear that is not resolved within 4 weeks of Visit 1 and led to a change in asthma management or, 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.
5. Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has clinical visual evidence of candidiasis at Visit 1.
6. Concurrent Diseases/ Abnormalities: Any significant abnormality or medical condition identified at the screening medical assessment (including serious psychological disorder) likely to interfere with the conduct of the study.
7. Allergies:
Drug allergies: Any adverse reaction including immediate or delayed
hypersensitivity to any beta2-agonist, sympathomimetic drug. Known or suspected sensitivity to the constituents of the NDPI (including lactose and magnesium stearate).
Milk Protein Allergy: History of severe milk protein allergy.
8. Tobacco use: Present use of any tobacco products.
9. Affiliation with Investigator Site: A subject will not be eligible for this study if he/she is an immediate family member of the participating Investigator, sub-Investigator, study coordinator, or employee of the participating Investigator.
10. Previous Exposure to Investigational Product: Subjects who have previously been exposed to VI including in clinical studies HZA112776 or HZA112777.
11. Parental/Guardian Factors: Parent or Guardian with a history of psychiatric disease, intellectual deficiency, substance abuse or other condition (e.g. inability to read, comprehend or write) which may affect:
• validity of consent to participate in the study
• adequate supervision of the subject during the study
• compliance of subject with study medication and study procedures (e.g. completion of daily diary, attending scheduled clinic visits)
• subject safety and well-being
12. Children in Care: Children who are wards of the government or state are not eligible for participation in this study. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The primary endpoint will be the mean change from baseline in daily
pre-dose (i.e. dosing trough) PM PEF from patient electronic daily diary
averaged over the 4 week treatment period.
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Average of daily pre-dose PM PEF over the 4 week treatment period. |
|
| E.5.2 | Secondary end point(s) |
Change from baseline in evening clinic visit trough (pre bronchodilator
and predose) FEV1 at the end of the 4 week treatment period in children
who can perform the manoeuvre.
• Change from baseline in the percentage of rescue-free 24 hour periods
during the 4-week treatment period.
• Change from baseline in daily AM PEF averaged over the 4-week
treatment period.
• Change from baseline in PM PEF at Endpoint (Endpoint is defined as
the mean over the last 7 days of the treatment period).
• Change from baseline in AM PEF at Endpoint (Endpoint is defined as
the mean over the last 7 days of the treatment period).
• Change from baseline in the percentage of symptom-free 24-hour
periods during the 4-week treatment period.
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| FEV1, rescue freed days, PM PEF, AM PEF, and Symptom Free days evaluated during the 12-week treatment period. Pre dose AM PEF evaluated at Endpoint (Endpoint is defined as the mean over the last 7 days of treatment). |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Argentina |
| Brazil |
| Chile |
| Mexico |
| Peru |
| Philippines |
| United States |
|
| 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
|
|
| 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 | 12 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 12 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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