| 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 |
| To assess the safety and tolerability of 12 months treatment with two strengths of Fluticasone Furoate/GW642444 Inhalation Powder once-daily in the evening in subjects 12 years of age and older with asthma. |
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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 |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1.Type of Subject: Outpatient
2.Age: 12 years of age or older at Visit 1 (or 18 years of age or older if local regulations or the regulatory status of study medication permit enrolment of adults only).
3.Gender: Male or eligible female
To be eligible for entry into the study, females of childbearing potential must commit to consistent and correct use of an acceptable method of birth control, 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 levonorgetrel or etonogestrel
•Injectable progestogen
•Oral contraceptive (either combined estrogen/progestin or progestin only)
•Any intrauterine device (IUD) with a documented failure rate of less than
1% per year
•Estrogenic vaginal ring
•Double barrier method – spermicide plus a mechanical barrier (e.g. spermicide plus a male condom or spermicide and female diaphragm)
•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), Visit 6, Visit 8, and Visit 11/Early Withdrawal. A urine pregnancy test will be performed at Visits 2 through 5, Visit 7, Visit 9, Visit 10 and follow-up contact.
4.Asthma Diagnosis: A diagnosis of asthma as defined by the National Institutes of Health [NIH, 2007] at least 12 weeks prior to Visit 1.
5.Severity of Disease: A best FEV1 of ≥50% of the predicted normal value at Visit 1. NHANES III predicted values will be used for subjects ≥12 years of age [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 African American/African Heritage race, then the African American equations will be used. Otherwise, the Caucasian equations will be used.
6.Reversibility of Disease: Historical documentation within 12 months or currently demonstrated a ≥12% and ≥200mL reversibility of FEV1 within approximately 10 to 40 minutes following 2 to 4 inhalations of albuterol/salbutamol inhalation aerosol (if required, spacers are permitted for reversibility testing only) or equivalent nebulized treatment with albuterol/salbutamol solution at screening.
7.Current Anti-Asthma Therapy: Subjects must be using an approved dose of an ICS (as per specific prescribing information) with or without an additional controller medication (i.e., long-acting beta-agonist, leukotriene modifier, etc.) for at least four weeks prior to Visit 1. See Table 1 in protocol for examples of allowed doses of commonly used ICS.
8.Short-Acting Beta2-Agonists: All subjects must be able to replace short-acting beta2-agonists with albuterol/salbutamol inhalation aerosol at Visit 1 for use as needed for the duration of the study. The use of spacer device with MDI or nebulized albuterol/salbutamol will not be allowed during the study with the exception of their use during reversibility testing at Visit 1. Subjects must be able to withhold all inhaled short-acting beta-sympathomimetic bronchodilators for at least 6 hours prior to study visits.
9.Informed Consent: All subjects must be able and willing to give written informed consent to take part in the study.
10.Compliance: Subjects must be able to comply with all the study requirements including clinic visit schedules and completion of diary cards.
Prior to randomisation the subject must meet the following criteria (at Visit 2):
•LOCS III grades of nuclear opalescence (NO) ≤3.0, nuclear color (NC) ≤3.0, cortical (C) ≤2.0, and posterior subcapsular opacity (P) ≤0.5 at baseline for both eyes (Pupils must be maximally dilated prior to LOCS III grading. The maximal size of the dilated pupil must be ≤6mm) .
•Intraocular Pressure ≤20mmHg for both eyes.
•Funduscopic: Horizontal cup-to-disc ratio (expressed as a percent) of ≤66% in both eyes.
•Visual Acuity: A best-corrected distance visual acuity of ≤0.18 on LogMAR (logarithm of the Minimum Angle of Resolution) scale using the Early Treatment Diabetic Retinopathy Study (ETDRS) charts in both eyes measured separately.
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| E.4 | Principal exclusion criteria |
Subjects meeting any of the following criteria must not be enrolled in the study:
1.History of Life-Threatening Asthma: i.e. an asthma episode that required intubation and/or was associated with hypercapnea, respiratory arrest or hypoxic seizures in the past 5 years.
2.Asthma Exacerbation requiring systemic corticosteroids within 3 months of Visit 1 or overnight hospitalization for asthma within 6 months prior to Visit 1.
3.Concurrent Respiratory Disease: pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or respiratory abnormalities other than asthma.
4.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 results if the condition/disease exacerbated during the study (see protocol for further detail).
5.Visual evidence of oral candidiasis
6.Participation in a study or use of an investigational drug within 30 days prior to Visit 1 or within ten half-lives (t1/2) of the prior investigational study (whichever is longer of the two).
7.Previous Participation: previous randomization to treatment in a Phase III Fluticasone Furoate/GW642444 Inhalation Powder study (if a subject is a screen failure or run-in failure from another Phase III Fluticasone Furoate/GW642444 Inhalation Powder study, they are eligible for this study).
8.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 Dry Powder Inhaler (i.e., lactose or magnesium stearate).
9.Milk Protein Allergy: History of severe milk protein allergy.
10.Immunospressive medications: use of or requirement for 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.
11.Attendance: infirmity, disability or geographical location which seems likely (in the opinion of the investigator) to impair compliance with any aspect of this study protocol or scheduled visits to the study center and non-compliance with study medication or procedures (i.e., completion of diary card).
12.Neurological or psychiatric disease or history of drug or alcohol use which would interfere with the subject’s proper completion of the protocol requirements.
13.Concomitant Medications: Administration of prescription or over the counter medication which would significantly affect the course of asthma, or interact with sympathomimetic amines
14.Use of inhaled tobacco products within the past three months or historical use of 10 pack years or more.
15.Immediate family member of the participating investigator, sub-investigator, study coordinator, or employee of the participating investigator.
16.Administration of systemic, oral or depot corticosteroids within 12 weeks of Visit 1.
17.A subject is not eligible if he/she is receiving a potent CYP 3A4 inhibitor within 4 weeks of Visit 1 (e.g., ritonavir, ketoconazole, itraconazole).
18.Nightshift Workers.
Exclusion Criteria for Randomization to Treatment (at Visit 2)
1.Change (increase or decrease) in Visit 2 absolute FEV1 of >20% compared with FEV1 at Visit 1.
2.Clinically significant abnormal laboratory tests during Visit 1, which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present.
3.Changes in asthma medication (excluding albuterol/salbutamol inhalation aerosol provided at Visit 1) occurring between Visits 1 and 2.
4.Occurrence of a culture-documented or suspected bacterial or viral infection of the upper or lower respiratory tract, sinus or middle ear during the run-in period that 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.Evidence of significant abnormality in the 12-lead ECG performed at Visit 1. Selected specific ECG findings that are considered to be significant and will exclude the subject from study participation (see protocol for further detail). •
6.Evidence of significant abnormality in the 24-hour 12-lead Holter monitoring performed at Visit 1. Investigators will be provided with Holter reviews conducted by an independent cardiologist to assist in evaluation of subject eligibility.
7.Asthma exacerbation requiring in-patient hospitalization or emergency department visit between Visits 1 and 2.
8.Clinical visual evidence of oral candidiasis
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| No specific safety endpoint has been defined as primary; a holistic approach is taken to assess the objective defined above with all safety endpoints being of equal importance. The relative safety of each Fluticasone Furoate/GW642444 Inhalation Powder group and fluticasone propionate 500mcg twice daily will be evaluated by assessing the overlap in the confidence intervals for the treatment effects relative to a marketed benchmark, fluticasone propionate. Statistical modelling will be performed, where appropriate, in order to provide greater understanding for some endpoints. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | No |
| 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 |
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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 |
| Fluticasone Propionate 500 mg |
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| 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 |
| Thailand |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 23 |
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