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 |
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.
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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 of the study is to compare the efficacy and safety of FF/GW642444 Inhalation Powder 100mcg/25mcg and FF 100mcg both administered once daily in the evening in adolescent and adult subjects 12 years of age and older with persistent bronchial asthma over a 12 week treatment period. |
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E.2.2 | Secondary objectives of the trial |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
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. For sites in the
following countries subjects will be ≥18 years of age: Germany and any other
countries where local regulations or the regulatory status of study medication permit
enrolment of adults only. Subjects must have 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 12-17 years.
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 trial and for a period after the trial to account for elimination of the drug (minimum of six days)
•Female subjects should not be enrolled 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 7 or Early Withdrawal. In addition a urine pregnancy test will be performed on all females of childbearing potential at randomisation (Visit 3) and Follow-up Visit (Visit 8).
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.
Please see page 21 of the Protocol for the populations that are eligible for enrolment based on their current Anti-Asthma medication.
7.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.
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E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in the run-in period for this study if any of following criteria apply:
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. Please see page 22 of Protocol for the list of additional excluded conditions/ diseases
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 fluticasone furoate/GW642444 combination product study (i.e., HZA106829, 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) |
Co-primary efficacy endpoints
•Change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the 84-day treatment period in all subjects.
•Weighted mean serial FEV1 over 0-24 hours post-dose calculated in the subset of subjects performing serial FEV1 at the end of the double-blind treatment period. 24-hour serial FEV1 will include pre-dose assessment within 5 minutes prior to dosing, and post-dose assessments after 5, 15, 30 minutes and 1, 2, 3, 4, 5, 12, 16, 20, 23 and 24 hours.
Please refer to page 11 of Protocol |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
•Mean change from baseline in clinic visit trough (pre-bronchodilator and pre-dose) FEV1 at the end of the 84-day treatment period in all subjects.
•Weighted mean serial FEV1 over 0-24 hours post-dose calculated in the subset of subjects performing serial FEV1 at the end of the 84-day treatment period. 24-hour serial FEV1 included pre-dose assessment within 5 minutes prior to dosing, and 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.5.2 | Secondary end point(s) |
Powered secondary efficacy endpoint
• Change from baseline in the percentage of rescue-free 24 hour periods during the 12-
week treatment period.
Secondary efficacy endpoints
• Change from baseline in the percentage of symptom-free 24 hour periods during the
12-week treatment period
• Change from baseline in total AQLQ (+12) score at the end of 12-week treatment
period
• The number of withdrawals due to lack of efficacy during the 12-week treatment
period. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
•Mean change from baseline in the percentage of rescue-free 24-hour periods during the 12-week treatment period.
•Change from baseline in the percentage of symptom-free 24-hour periods during the 12-week treatment period.
•Change from baseline in total AQLQ (+12) score at the end of the 12-week treatment period.
•The number of withdrawals due to lack of efficacy during the 12-week treatment period.
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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 | 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 | 3 |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
Japan |
Ukraine |
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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E.8.9 Initial estimate of the duration of the trial |
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 | 2 |
E.8.9.2 | In all countries concerned by the trial days | 0 |