| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 12.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10003553 |
| E.1.2 | Term | Asthma |
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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 compare the efficacy and safety of FF/GW642444 Inhalation Powder 200mcg/25mcg administered once daily each evening to FF Inhalation Powder 200mcg administered alone once daily each evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma over a 24 week treatment period.
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| E.2.2 | Secondary objectives of the trial |
The secondary objective of this study is to compare the efficacy of FF 200mcg administered once daily each evening with FP 500mcg administered twice daily.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Informed consent: Subjects must give their signed and dated written informed consent to participate.
2. Type of Subject: Outpatients 12 years of age or older at Visit 1 (or ≥18 years of age if local regulations or the regulatory status of study medication permit enrolment of adults only [e.g., countries within the European Union]) with a diagnosis of asthma as defined by the National Institutes of Health [NIH, 2007] at least 12 weeks prior to Visit 1.
N.B. Target to randomise approximately 15% of subjects aged 12-17years.
3. Gender: Male or Eligible Female, defined as non-childbearing potential or childbearing potential using an acceptable method of birth control consistently and correctly, as defined by the following:
• Male partner who is sterile prior to the female subject’s entry into the study and is the sole sexual partner for that female subject
• Implants of levonorgestrel, etonogestrel
• Injectable progestogen
• Oral contraceptive (either combined oestrogen/progestin or progestin only)
• Any intrauterine device (IUD) with a documented failure rate of less than 1% per year
• Double barrier method – spermacide plus a mechanical barrier (e.g., spermacide plus a male condom or a spermacide and female diaphragm).
• Oestrogenic vaginal ring
• Percutaneous contraceptive patches
• Females of childbearing potential who are not sexually active must commit to complete abstinence from intercourse throughout the clinical study and for a period after the study to account for elimination of the drug (minimum of six days)
• Female subjects should not be enrolled if they if they are pregnant, lactating or plan to become pregnant during the time of study participation. A serum pregnancy test is required for females of childbearing potential at the initial screening visit (Visit 1) and Visit 10 or Early Withdrawal. In addition a urine pregnancy test will be performed on all females of childbearing potential at randomisation (Visit 3) and subjects will be given a home urine pregnancy kit at Visit 10 for use during the follow-up period.
4. Severity of Disease: A best pre-bronchodilator FEV1 of 40%-90% of the predicted normal value at the Visit 1 screening visit. Predicted values will be based upon NHANES III [Hankinson, 1999]. If a subject is recorded as having Hispanic or Latino ethnicity, then the Mexican-American equations will be used (irrespective of race). If a subject is recorded as being of African-American/African heritage race, then the African-American equations will be used. If a subject is recorded as being of Asian race, then the Asian adjustment will be used [Hankinson, 2010]. Otherwise, the Caucasian equations will be used.
5. Reversibility of Disease: Demonstrated ≥12% and ≥200mL reversibility of FEV1 within 10-40 minutes following 2-4 inhalations of albuterol/salbutamol inhalation aerosol (or equivalent nebulized treatment with albuterol/salbutamol solution) at the Screening Visit.
6. Current Anti-Asthma Therapy: All subjects must be using an ICS with or without LABA for at least 12 weeks prior to Visit 1.
Two populations are eligible for enrolment:
Subjects maintained on a stable ICS dose (FP 500mcg twice daily or equivalent) for 4 weeks prior to Visit 1.
OR
Subjects maintained on a stable dose of an ICS/LABA mid-dose combination product (e.g., Seretide/Advair 250/50 twice daily or equivalent via other combination products or via separate inhalers) for at least 4 weeks prior to Visit 1. Subjects taking Symbicort as needed must switch to Symbicort maintenance dosing with use of a short acting beta2 agonist (SABA) for symptom relief at least 4 weeks prior to Visit 1.
LABA therapy is not permitted beginning on the day of Visit 1. Combination therapy must be stopped at Visit 1 and subjects switched to the same ICS dose for the run-in period.
See Table 1 page 20 of the protocol, for examples of doses of commonly prescribed ICS and ICS/LABA combination medication. Dosing regimen (once or twice daily to equal the total daily dose shown below) should be restricted to the current local product datasheets.
7. Short-Acting Beta2-Agonists (SABAs): All subjects must be able to replace their current SABA treatment with albuterol/salbutamol aerosol inhaler at Visit 1for 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.
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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 and/or was associated with hypercapnia, respiratory arrest or hypoxic seizures within the last 10 years.
2. Respiratory Infection: 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.
3. Asthma Exacerbation: Any asthma exacerbation requiring oral corticosteroids
within 12 weeks of Visit 1 or that resulted in overnight hospitalization requiring
additional treatment for asthma within 6 months prior to Visit 1.
4. Concurrent Respiratory Disease: A subject must not have current evidence of
pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease,
bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive
pulmonary disease, or other respiratory abnormalities other than asthma.
5. Other Concurrent Diseases/Abnormalities: A subject must not have any clinically
significant, uncontrolled condition or disease state that, in the opinion of the
investigator, would put the safety of the subject at risk through study participation or
would confound the interpretation of the efficacy results if the condition/disease
exacerbated during the study for further informaiton view protocol.
6. Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she
has clinical visual evidence of candidiasis at Visit 1.
7. Investigational Medications: A subject must not have used any investigational
drug within 30 days prior to Visit 1 or within five half-lives (t½) of the prior
investigational study (whichever is longer of the two).
8. Allergies:
• Drug Allergy: Any adverse reaction including immediate or delayed
hypersensitivity to any beta2-agonist, sympathomimetic drug, or any intranasal,
inhaled, or systemic corticosteroid therapy. Known or suspected sensitivity to
the constituents of the Novel DPI (i.e., lactose or magnesium stearate).
• Milk Protein Allergy: History of severe milk protein allergy.
9. Concomitant Medication:
• Administration of prescription or over the counter medication that would
significantly affect the course of asthma, or interact with study drug, such as:
anticonvulsants (barbiturates, hydantoins, carbamazepine); polycyclic
antidepressants; beta-adrenergic blocking agents; phenothiazines and
monoamine oxidase (MAO) inhibitors.
• Immunosuppressive Medications: A subject must not be using or require use
of immunosuppressive medications during the study.
Note: Immunotherapy for the treatment of allergies is allowed during the study
provided it was initiated 4 weeks prior to Visit 1 and subjects remain in the
maintenance phase for the duration of the study.
• Cytochrome P450 3A4 (CYP3A4) inhibitors: Subjects who have received a
potent CYP3A4 inhibitor within 4 weeks of Visit 1(e.g., ritonavir, ketoconazole,
itraconzole).
10. Compliance: A subject will not be eligible if he/she or his/her parent or legal
guardian has any infirmity, disability, disease, or geographical location which seems
likely (in the opinion of the Investigator) to impair compliance with any aspect of
this study protocol, including visit schedule and completion of the daily diaries.
11. Tobacco Use: Current smoker or a smoking history of 10 pack-years (e.g. 20
cigarettes/day for 10 years). A subject may not have used inhaled tobacco products
within the past 3 months (i.e., cigarettes, cigars, or pipe tobacco).
12. 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,
sub-Investigator, study coordinator, or employee of the participating Investigator.
13. Previous Participation: A subject may not have previously been randomised to
treatment in another Phase III FF/GW642444 combination product study (i.e.,
HZA106827, HZA106837, HZA106839, HZA106851, HZA113091).
14. Night shift workers: No subject is permitted to perform night shift work for 1 week prior to Visit 1 until completion of the study treatment period |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the 168-day treatment period in all subjects.
• Weighted mean serial FEV1 over 0-24 hours post-dose calculated in a subset of subjects (see Section 6.2.1) at the end of the 168-day treatment period. 24-hour serial FEV1 will include post-dose assessments after 5, 15, 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23 and 24 hours.
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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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| 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) | 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| stratified + double-dummy |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Yes |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | Yes |
| E.8.2.3.1 | Comparator description |
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| 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 | Information not present in EudraCT |
| 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 |
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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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| LSLV defined as end of 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 | 0 |
| 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 | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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