A Study to Compare the Efficacy and Safety of Fluticasone Furoate (FF) 100 mcg Once Daily With Fluticasone Propionate (FP) 250 mcg Twice Daily (BD) and FP 100 mcg BD in Well-controlled Asthmatic Japanese Subjects

Asthma Clinical Trial

Official title:

201135 : A Randomised, Double-blind, Multicenter, Parallel-group Study to Compare the Efficacy and Safety of Fluticasone Furoate (FF) 100 mcg Once Daily With Fluticasone Propionate (FP) 250 mcg Twice Daily (BD) and FP 100 mcg BD in Well-controlled Asthmatic Subjects Stepped Down From a Maintenance Therapy With RELVAR® Inhaler (FF/VI) 100/25 mcg Once-daily in Japanese Subjects

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02094937
• Other study ID #: 201135
• Status: Completed
• Phase: Phase 3
• First received: March 20, 2014
• Last updated: February 11, 2016
• Start date: March 2014
• Est. completion date: August 2015

Study information

• Verified date: February 2016
• Source: GlaxoSmithKline
• Contact: n/a
• Is FDA regulated: No
• Health authority: Japan: Ministry of Health, Labor and Welfare (MHLW) and Pharmaceuticals and Medical Devices Agency (PMDA)
• Study type: Interventional

Clinical Trial Summary

The primary aim of this study is to clarify the position of FF and FF/Vilanterol (VI) 100/25 micrograms (mcg) compared with existing therapies by assessing FF dosage equivalent to low to middle-dose inhaled corticosteroids (ICS). The study is divided into Run-in period, Period 1 (open-label treatment), Period 2 (double blind treatment) and Follow-up. Subjects with well controlled asthma after completing a run-in period of 4 weeks will be switched from middle-dose ICS/long acting beta 2 agonist (LABA) equivalent dose to once-daily FF/VI 100/25 mcg for an 8 weeks treatment period (Period 1). After this, subjects will be randomized in a 1:1:1 ratio to receive either FP 250 mcg twice daily, FP 100 mcg twice daily or FF 100 mcg once daily in a 12 week double blind treatment period (Period 2). There will be a 1 week Follow-up Period following completion of the double-blind treatment period, or early withdrawal from the study. Overall , the total duration of subject's participation in the study will be for 25 weeks. RELVAR is a registered trademark of the GSK group of companies.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 430
• Est. completion date: August 2015
• Est. primary completion date: August 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Informed consent: Subjects must give their signed and dated written informed consent to participate.

• Type of Subject: Outpatients 18 years of age or older at Visit 1. Subjects must have a diagnosis of asthma as defined by the National Institutes of Health at least 1 year prior to Visit 1.

• 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; Oral contraceptive (either combined estrogen/progestin); 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); 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 11 or Early Withdrawal. In addition a urine pregnancy test will be performed on all females of childbearing potential at Visit 2, Visit 5 and Visit 12.

• Severity of Disease: A best pre-bronchodilator FEV1 of >=80% of the predicted normal value at the screening visit (Visit 1). Predicted values will be based upon National Health and Nutrition Examination Survey (NHANES) III. As subjects are Asian, the Asian adjustment will be used.

• Stable Asthma: Subjects must have stable asthma, as judged by the Investigator. This includes no change in asthma medication for at least 8 weeks prior to Visit 1 and an ACT score of >=20 at Visit 1.

• Current Anti-Asthma Therapy: All subjects must be using the middle-dose ICS/LABA which is equivalent to twice-daily combination of fluticasone propionate and salmeterol 250 mcg for at least 12 weeks prior to the registration visit. In addition, the prescription of the middle-dose ICS/LABA shouldn't be changed at least 8 weeks prior to Visit 1.

• Short-Acting Beta2-Agonists (SABA): All subjects must be able to use salbutamol aerosol inhaler which will be provided as a rescue medication at Visit 1 during the study as needed. Subjects must be able to avoid using salbutamol for at least 6 hours prior to study visits.

• 12-lead electrocardiogram (ECG): Evidence of significant normality in the 12-lead ECG performed at Visit 1, as judged by the investigator Selected specific ECG findings that are not considered to be significant and will not exclude the subject from study participation include, but are not limited to, the following: T interval corrected for heart rate (QTc) <450 milliseconds (msec) or QTc <480 msec for patients with bundle branch block. The QTc is the QT interval corrected for heart rate according to Fridericia's formula (QTcF), machine overread. The QTc should be based on single or averaged QTc values of triplicate electrocardiograms (ECGs) obtained over a brief recording period. If there are any clinically significant abnormalities including but not limited to a T interval for heart rate (QT) prolonged, confirm with two additional ECGs taken.

Other inclusion criteria at Visit 2 and Visit 5:

• Subjects whose asthma meets the criterion of "well-controlled" (as defined in the protocol), and in the Investigators judgement it is acceptable for subject to "switch (Visit 2)" and "step-down (Visit 5)" in one week prior to Visit 2 or Visit 5.

• Compliance rate of the middle-dose ICS/LABA which is equivalent to twice-daily combination of fluticasone propionate and salmeterol 250 mcg (Visit1- Visit 2) and FF/VI 100/25 mcg (Visit 2 - Visit5) should be achieved >=80%

• Compliance with completion of both morning and evening eDairy data fulfils >=5days in one week prior to Visit 2 and Visit 5.

Exclusion Criteria:

• 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.

• 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 8 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.

• Asthma Exacerbation: Any asthma exacerbation requiring systemic corticosteroids or injection within 12 weeks of Visit 1 or that resulted in overnight hospitalization requiring additional treatment for asthma within 6 months prior to Visit 1.

• 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.

• 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. The list of additional excluded conditions/diseases includes, but is not limited to the following: congestive heart failure, known aortic aneurysm, clinically significant coronary heart disease, clinically significant cardiac arrhythmia, stroke within 3 months of Visit 1, uncontrolled hypertension (two or more measurements with systolic BP >160 millimeters of mercury (mmHg), or diastolic BP >100mmHg), recent or poorly controlled peptic ulcer, haematologic, hepatic, or renal disease, immunologic compromise, current malignancy (history of malignancy is acceptable only if subject has been in remission for one year prior to Visit 1 (remission = no current evidence of malignancy and no treatment for the malignancy in the 12 months prior to Visit 1)), tuberculosis (current or untreated) [Subjects with a history of tuberculosis infection who have completed an appropriate course of antituberculous treatment may be suitable for study entry provided that there is no clinical suspicion of active or recurrent disease], Cushing's disease, Addison's disease, uncontrolled diabetes mellitus, uncontrolled thyroid disorder, recent history of drug or alcohol abuse

• Oropharyngeal Examination: A subject will not be eligible for the run-in if he/she has clinical visual evidence of candidiasis at Visit 1.

• Investigational Medications: A subject must not have used any investigational drug within 30 days prior to Visit 1 or within five half-lives (t1/2) of the prior investigational study (whichever is longer of the two).

• 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 investigational product (i.e., lactose or magnesium stearate); Milk Protein Allergy: History of severe milk protein allergy.

• 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 at least 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.,Clarithromycin, atazanavir, indinavir, itraconazole, ketoconazole, nefazadone, nelfinavir; ritonavir; saquinavir; telithromycin, troleandomycin, voriconazole, mibefradil, cyclosporine, etc).

• 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 eDiaries and a paper medical conditions diary.

• 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).

• 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.

Other exclusion criteria at Visit 2 and Visit 5:

• Evidence of clinically significant abnormal laboratory tests during Visit 1which are still abnormal upon repeat analysis and are not believed to be due to disease(s) present. Each Investigator will use his/her own discretion in determining the clinical significance of the abnormality.

• Changes in asthma medication (excluding salbutamol inhalation aerosol provided at Visit 1).

• 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 and the open-label treatment 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.

• Any asthma exacerbation requiring systemic corticosteroids or injection or that resulted in overnight hospitalization requiring additional treatment for asthma. Clinical visual evidence of oral candidiasis at Visit 2 and Visit 5.

• Positive urine pregnancy test for all females of childbearing potential at Visit 2 and Visit 5

• Subjects that the investigator decides that it is impossible for subject to do "switch (Visit 2)" and "step-down (Visit 5)".

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Related Conditions & MeSH terms

• Asthma

Intervention

Drug:
• Fluticasone Furoate/Vilanterol
FF/VI 100mg/25 mcg is available as a dry white powder to be given once daily in the evening via dry powder inhaler
• Fluticasone Furoate 100 mcg
FF 100 mcg is available as a dry white powder to be given once daily in the evening via dry powder inhaler
• Fluticasone Propionate 250 mcg
FP 250 mcg is available as a dry white powder to be given twice daily (morning and evening) via dry powder inhaler
• Fluticasone Propionate 100 mcg
FP 100 mcg is available as a dry white powder to be given twice daily (morning and evening) via dry powder inhaler
• Fluticasone Furoate Placebo
Matching placebo of Fluticasone Furoate will be given once daily in the evening via dry powder inhaler
• Fluticasone Propionate Placebo
Matching placebo of Fluticasone Propionate will be given twice daily (morning and evening) via dry powder inhaler

Locations

Country	Name	City	State
Japan	GSK Investigational Site	Aomori
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Fukuoka
Japan	GSK Investigational Site	Gifu
Japan	GSK Investigational Site	Hiroshima
Japan	GSK Investigational Site	Hyogo
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Ibaraki
Japan	GSK Investigational Site	Kagawa
Japan	GSK Investigational Site	Kagawa
Japan	GSK Investigational Site	Kagawa
Japan	GSK Investigational Site	Kagawa
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kanagawa
Japan	GSK Investigational Site	Kochi
Japan	GSK Investigational Site	Kyoto
Japan	GSK Investigational Site	Mie
Japan	GSK Investigational Site	Mie
Japan	GSK Investigational Site	Oita
Japan	GSK Investigational Site	Osaka
Japan	GSK Investigational Site	Saitama
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo
Japan	GSK Investigational Site	Tokyo

Sponsors (1)

Lead Sponsor	Collaborator
GlaxoSmithKline

Country where clinical trial is conducted

Japan, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Time to withdrawal due to poorly -controlled (requires step-up) asthma during Period-2	Poorly-controlled asthma is defined as 3 or more of the following: day-time symptom score of >=1 on more than 2 days; 2 or more days of rescue salbutamol use; morning peak expiratory flow (PEF) of <80% of the best effort value on one or more days; a best pre-bronchodilator forced expiratory volume in one second (FEV1) of <80% of the predicted normal value at any visit; night-time symptom score of >=1. Also, subject with asthma worsening or exacerbations will be considered as poorly-controlled.	Week 8 to Week 20	No
Primary	Proportion of subjects with well-controlled asthma at the end of Period-2	Well-controlled asthma is defined as 2 or more of the following when assessed weekly: day-time symptom score of >=1 on no more than 1 day; no more than 1day of rescue salbutamol use; morning PEF of >=80% of the best effort value every day. And no night time awakenings, asthma worsening or exacerbations when assessed daily. Also, a best pre-bronchodilator FEV1 of >=80% of the predicted normal value at any visit.	20 Weeks	No
Secondary	Mean change from baseline in clinic visit trough FEV1 at the end of Period-2	Electronic spirometry will be used to measure trough FEV1. Baseline value will be the pre-dose value at randomization.	Week 20	No
Secondary	Mean change from baseline in daily morning and evening peak expiratory flow (PEF) averaged during Period-2	PEF will be measured each morning and evening prior to study medication and any rescue salbutamol inhalation aerosol use using an electronic peak flow meter. Baseline will be the mean of the daily values in one week prior to randomization	Week 8 to Week 20	No
Secondary	Mean change from baseline in the percentage of symptom-free 24-hour periods during Period-2	Subjects who will be symptom free for 24-hours will be assessed. Baseline will be the mean of the daily values in one week prior to randomization	Week 8 to Week 20	No
Secondary	Mean change from baseline in the percentage of rescue-free 24-hour periods during Period-2	The time span during which the subjects will not have to take any rescue medication (medication intended to relieve symptoms immediately) will be considered as a rescue free period. Baseline will be the mean of the daily values in one week prior to randomization.	Week 8 to Week 20	No
Secondary	Mean change from baseline in Asthma Control Test (ACT) score during Period-2	ACT is a 5 question test with various responses rating frequency of asthma events over 4-week period. The questions are designed to be self-completed by the subject. Baseline value will be the pre-dose value at randomization.	Week 8 to Week 20	No
Secondary	Proportion of subjects with ACT score >=20 at the end of the Period-2	The proportion of subjects with ACT score >=20 at the end of the Period-2 will be analyzed using a logistic regression model including terms for baseline, gender, age and treatment group.	Week 20	No