Clinical trial NCT01978119: A Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Combination Dry Powder of Fluticasone Propionate and Salmeterol (FSC) 250/50 Microgram (mcg) Twice Daily (BID) in Adults and Adolescents With Asthma
Official title: A Randomised, Multi-Centre, Double-Blind, Double-Dummy, Two Way Cross-Over, Twelve Weeks Non-inferiority Study to Evaluate the Efficacy, Safety, and Tolerability of Combination Dry Powder of Fluticasone Propionate and Salmeterol 250/50 mcg Twice Daily Delivered Through a Capsule-Based Inhaler and a Multi-Dose Inhaler in Adults and Adolescents With Asthma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Asthma
Keywords: Multi-Dose Inhaler
safety
Asthma
efficacy
pharmacodynamics
fluticasone propionate/salmeterol (FSC) 250/50 mcg
tolerability
Capsule-Based Inhaler
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-11-07
Enrollment: 124
Sex: ALL
Minimum age (years): 12
Maximum age (years): 80
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: This is a multi-centre, randomised, double-blind, double-dummy, two way cross-over, 12 week non inferiority study to evaluate the efficacy, safety, and tolerability of FSC 250/50 mcg capsule-based inhaler and FSC 250/50 mcg multi-dose inhaler each administered BID in adults and adolescents with asthma. The primary objective of this study is to demonstrate that FSC 250/50 mcg administered BID by capsule-based inhaler is non-inferior compared to FSC 250/50 mcg administered BID by multi-dose inhaler . The study consists of six phases: Pre-screening, Screening/Run-in (3 weeks), Treatment Period 1 (12 weeks), Washout (minimum 3 weeks), Treatment Period 2 (12 weeks) and Follow-up (1 week). The total duration of the study for each subject will be at least 31 weeks.


Eligibility criteria: Inclusion Criteria:

* Male or female \>=12 and \<=80 years of age at the time of signing the informed consent
* A female subject is eligible to participate if she is of:
* Non-childbearing potential defined as premenopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \>40 milli international unit per milliliter (mIU/mL) and oestradiol \<40 picogram (pg)/mL \[\<147 picomole per liter (pmol/L)\] is confirmatory); Females on hormone replacement therapy (HRT) and whose menopausal status is in doubt will be required to use one of the contraception methods (i.e., in accordance with the approved product label and the instructions of the physician for the duration of the study from Screening to follow-up contact) if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of postmenopausal status before study enrolment. For most forms of HRT, at least 2 to 4 weeks should elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. After confirmation of their postmenopausal status, they can resume use of HRT during the study without use of a contraceptive method; child-bearing potential and is abstinent or agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) before the start of dosing to sufficiently minimise the risk of pregnancy at that point. Female subjects must agree to use contraception until at least 2 days post the last dose of study treatment; abstinence from penile-vaginal intercourse must be consistent with the preferred and usual lifestyle of the subject.
* Severity of disease: A best prebronchodilator FEV1 of \>=40% to \<=85% of the predicted normal value at Visit 1 (Screening and Run-in Visit). Predicted values will be based upon National Health and Nutrition Examination Survey (NHANES) III. 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. Otherwise, the Caucasian equations will be used.
* Reversibility of disease: Demonstrated \>=12% and \>=200 mL reversibility of FEV1 within 10 to 40 minutes after 2 to 4 inhalations of salbutamol inhalation aerosol (or equivalent nebulised treatment with salbutamol solution) at Visit 1 (Screening and Run-in Visit).
* Current anti-asthma therapy: All subjects must be using an Inhaled Corticosteroid (ICS) with or without long-acting beta-adrenergic agonist (LABA) for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit). Two populations are eligible for enrolment: - Subjects maintained on ICS monotherapy (FP 100 mcg to 250 mcg BID or equivalent) for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit) or Subjects maintained on an ICS/LABA combination product (e.g., Fluticasone propionate/salmeterol 100/50 or 250/50 mcg BID or equivalent by other combination products or by separate inhalers) for at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit). Subjects taking budesonide/formoterol or beclomethasone/formoterol as needed must switch to budesonide/formoterol maintenance dosing (excluding the highest dose) with use of a SABA for symptom relief at least 8 weeks and a stable dose for at least 4 weeks before Visit 1 (Screening and Run-in Visit). NOTE: Subjects on low dose ICS monotherapy should only be enrolled, if, in the opinion of the investigator, after review of their medical history and clinical examination, they will be able to benefit from both an increase in ICS dose and the addition of LABA therapy arising from and ICS/LABA combination.
* Ability to withhold LABA therapy: Other than what is provided during the study, LABA therapy is not permitted on the day of Visit 1 (Screening and Run-in Visit) and throughout the entire study. The last dose of LABA and LABA/ICS combinations are to be taken on the day before Visit 1. Sites should contact the medical monitor to discuss subject eligibility, for doses of commonly prescribed ICS and ICS/LABA combination medication; as mentioned in the study protocol.
* SABA: All subjects must be able to replace their current SABA treatment with rescue salbutamol/albuterol at Visit 1 (Screening and Run-in Visit) for use as needed for the duration of the study. Subjects must be able to withhold salbutamol/albuterol for at least 6 hours before each study visit.
* Liver safety criteria: Alanine aminotransferase (ALT) \<=2 the upper limit of normal (ULN), Alkaline phosphatase and bilirubin \<=1.5 ULN (isolated bilirubin \>1.5 ULN is acceptable if bilirubin is fractionated and direct bilirubin is \<35%) at Visit 1 (Screening and Run-in Visit).
* Electrocardiogram (ECG) safety criteria: The subject must have no ECG abnormalities that would, in the opinion of investigator, compromise subject safety, or significantly affect subject's ability to complete the trial. As such, the investigator will determine the clinical significance of any ECG abnormality and determine if a subject is precluded from entering the study. At Visit 1 (Screening and Run-in Visit), ECG safety criteria must be: QT interval corrected for heart rate (QTc) or QT interval corrected for heart rate according to Fridericia formula (QTcF) \<450 msec or QTc \<480 msec for subjects with bundle branch block; Investigators will be responsible for ensuring appropriate clinical interpretation of ECGs.
* The subject and/or the subject's legal guardian (if applicable) must be capable of giving informed consent/assent, which includes compliance with the study requirements and restrictions listed in the consent/assent form.

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 4 weeks of Visit 1 (Screening and Run-in Visit) 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 ability to participate in the study
* Asthma exacerbation: Any asthma exacerbation requiring oral corticosteroids within 12 weeks of Visit 1 (Screening and Run-in Visit) or that resulted in overnight hospitalisation requiring additional treatment for asthma within 6 months before Visit 1 (Screening and Run-in Visit)
* 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. Additional excluded conditions/diseases are included in the study protocol
* Evidence of a severe exacerbation, defined as deterioration of asthma requiring the use of systemic corticosteroids (tablets, suspension, or injection) for at least 3 days or an in-patient hospitalisation or emergency department visit due to asthma that required systemic corticosteroids between Visit 1 (Screening and Run-in Visit) and Visit 2 (randomisation and Treatment Period 1 Baseline Visit)
* Oropharyngeal examination: A subject will not be eligible for the Run-in if he/she has clinical visual evidence of candidiasis at Visit 1 (Screening and Run-in Visit)
* Investigational medications: A subject must not have administered any investigational drug within 30 days before Visit 1(Screening and Run-in Visit) or within five half-lives of the prior investigational drug (whichever is the longer of the two). The prior investigational drug half-life may be confirmed with the prior investigational study sponsor or by consulting relevant study documentation
* 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 FSC multi-dose inhaler and capsule-based inhaler (i.e., lactose), Milk protein allergy; History of severe milk protein allergy
* Concomitant medications: Administration of prescription or over the counter medication that would significantly affect the course of asthma, or interact with study treatment, 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
* Cytochrome P450 3A4 (CYP3A4) inhibitors: Subjects who have received a potent CYP3A4 inhibitor within 4 weeks of Visit 1(Screening and Run-in Visit) (e.g., ritonavir, ketoconazole, itraconazole)
* Subject is unable to refrain from the use of prescription or non-prescription drugs, including vitamins, herbal and dietary supplements (including St John's wort) within 7 days (or 14 days if the drug is a potential enzyme inducer) or five half-lives (whichever is longer) before the first dose of study treatment, unless in the opinion of the investigator and medical monitor the medication will not interfere with the study procedures or compromise subject safety
* Any subjects that have previously received or are currently receiving omalizumab
* Use of the excluded medications are included in the study protocol
* 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 that 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
* Tobacco use: Current smoker or a smoking history of ≥10 pack-years (e.g., 20 cigarettes/day for 10 years). A subject must not have used inhaled tobacco products within the past 3 months (e.g., cigarettes, cigars or pipe tobacco). One pack year is defined as 20 manufactured cigarettes (1 pack) smoked per day for 1 year
* Pregnant females as determined by urine test at Visit 1 (Screening and Run-in Visit) or predosing. A confirmatory serum pregnancy test is required if the urine test is questionable or positive
* Lactating females
* A positive hepatitis B surface antigen or positive hepatitis C test result
* Subject is mentally or legally incapacitated
* Child in Care (CiC): A CiC is a child who has been placed under the control or protection of an agency, organisation, institution or entity by the courts, the government or a government body, acting in accordance with powers conferred on them by law or regulation. The definition of a CiC can include a child cared for by foster parents or living in a care home or institution, provided that the arrangement falls within the definition above. The determination of whether a child meets the definition of CiC should be made with the study centre staff in consultation with the responsible institutional review board (IRB)/independent ethics committee (IEC).
* Unwillingness or inability to follow the procedures outlined in the protocol.

Primary outcomes:
measure: Change From Baseline in Trough Morning Forced Expiratory Volume in 1 Second (FEV1) at Day 85
timeFrame: Baseline and Day 85
Secondary outcomes:
measure: FEV1 Area Under the Curve From 0 to 12 Hours (AUC [0-12]) on Day 1 of Each Treatment Period
timeFrame: Day 1 of each Treatment Period
measure: FEV1 AUC (0-12) at Day 85 of Each Treatment Period
timeFrame: Day 85 of each Treatment Period
measure: Change From Baseline in Morning Trough FEV1 at Day 28 and Day 56
timeFrame: Baseline, Day 28, and Day 56
measure: Change From Baseline (BL) in Morning Peak Expiratory Flow Rate (PEFR) Over 12 Weeks (From Paper Diary Card) for Each Treatment Period(TP)
timeFrame: Baseline and up to Day 85 of each Treatment Period
measure: Change From Baseline (BL) in Rescue Medication Use Over 12 Weeks (From Paper Diary Card) for Each Treatment Period (TP)
timeFrame: Baseline and up to Day 85 of each Treatment Period
measure: Change From Baseline in Day-time(AM) and Night-time (PM) Asthma Symptoms(Sy) From Paper Diary Card (PDC) Over 12 Weeks(wk) for Each Treatment Period(TP)
timeFrame: Baseline and up to Day 85 of each Treatment Period
measure: Change From Baseline in the Percentage of Symptom-Free Days From Paper Diary Card Over 12 Weeks
timeFrame: Baseline and up to Day 85 of each Treatment Period
measure: Change From Baseline in Asthma Control Test (ACT) Over 12 Weeks for Each Treatment Period
timeFrame: Baseline and up to Day 85 of each Treatment Period
measure: Change From Baseline in the Percentage (%) of Rescue-free Days Over 12 Weeks (From Paper Diary Card) for Each Treatment Period(TP)
timeFrame: Baseline and up to Day 85 of each Treatment Period
Other outcomes:
Locations:
city: Nizhniy Novgorod
country: Russian Federation
facility: GSK Investigational Site
city: Penza
country: Russian Federation
facility: GSK Investigational Site
city: Ryazan,
country: Russian Federation
facility: GSK Investigational Site
city: Smolensk
country: Russian Federation
facility: GSK Investigational Site
city: Tomsk
country: Russian Federation
facility: GSK Investigational Site
city: Yaroslavl
country: Russian Federation
facility: GSK Investigational Site
city: Dnipropetrovsk
country: Ukraine
facility: GSK Investigational Site
city: Ivano-Frankivsk
country: Ukraine
facility: GSK Investigational Site
city: Kharkiv
country: Ukraine
facility: GSK Investigational Site
city: Odesa
country: Ukraine
facility: GSK Investigational Site
city: Vinnytsia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhia
country: Ukraine
facility: GSK Investigational Site
city: Zaporizhzhia
country: Ukraine
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References:
citation: Chan R, Sousa AR, Mallett S, Hynds P, Homayoun-Valiani F, Tabberer M, Mehta R. Assessment of the efficacy and safety of fluticasone propionate and salmeterol delivered as a combination dry powder via a capsule-based inhaler and a multi-dose inhaler in patients with asthma. Pulm Pharmacol Ther. 2016 Dec;41:19-24. doi: 10.1016/j.pupt.2016.09.002. Epub 2016 Sep 4.