A Randomised, Two Treatment, Four-Way Cross-Over (Replicate Design), Two Sequence, Repeat Dose Study in Patients With Moderate Asthma to Compare Pharmacokinetics and Pharmacodynamic Effects of Fluticasone Propionate and Salmeterol Delivered Via the Low Airflow Resistance Fluticasone Propionate/Salmeterol (100/50 mcg) ROTAHALER Inhaler Relative to Fluticasone Propionate/Salmeterol (100/50 mcg) Delivered Via the DISKUS Inhaler
Overview
- Phase
- Phase 1
- Intervention
- Fluticasone Propionate/Salmeterol Xinafoate DISKUS
- Conditions
- Asthma
- Sponsor
- GlaxoSmithKline
- Primary Endpoint
- Salmeterol maximum observed concentration (Cmax)
- Status
- Withdrawn
- Last Updated
- 11 years ago
Overview
Brief Summary
The Fluticasone Propionate/Salmeterol combination (FSC) at a dose of 100/50 micrograms (mcg) twice daily in DISKUS inhaler (also known as ACCUHALER®, Ddpi) inhaler is a recognised and licensed therapy for the treatment of asthma. GlaxoSmithKline (GSK) is developing the ROTAHALER/ ROTACAPS® (Rdpi) inhaler as an alternative treatment option for asthmatic patients. This study is a Phase I, randomised, double-blind, double-dummy, two- treatment, four-way cross-over (replicate design), two sequence, repeat dose, two centre study in mild to moderate asthmatics to compare the pharmacokinetics and pharmacodynamics of fluticasone proprionate/salmeterol (100/50 mcg) delivered via the Rdpi versus the Ddpi. A total of 58 subjects will be enrolled to ensure 52 subjects complete all dosing occasions. Each subject will be allocated to one of two treatment sequences and will participate in four treatment periods, receiving each of the treatments twice.
DISKUS, ACCUHALER, ROTAHALER and ROTACAPS are registered trademarks of GSK groups of companies.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Subjects with a known physician diagnosis of asthma with a best Forced Expiratory Volume in 1 Second (FEV1) of \>70% of the predicted normal value at the Screening visit. Percent predicted will be calculated using the European Respiratory Society Global Lung Function Initiative reference equations. Subjects must abstain from short acting beta-2 agonists (SABA) use for 6 hours prior to the Screening visit.
- •During the screening visit, subjects must either demonstrate the presence of reversible airway disease, defined as an increase in FEV1 of \>=12.0% over baseline and an absolute change of \>=200 millilitres (mL) within 60 minutes following 4 inhalations of albuterol/salbutamol inhalation aerosol (or equivalent nebulized treatment with albuterol/salbutamol solution) or in the absence of reversibility have documented evidence of a physician diagnosed asthma for at least 6 months
- •Male/females aged between 18 and 65 years of age inclusive, at the time of signing the informed consent.
- •Body weight \>= 50 kilograms (kg) and body mass index (BMI) within the range 18 - 35.0 kilogram/square meter (kg/m\^2) (inclusive).
- •A female subject is eligible to participate if she is of: Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy for this definition, "documented" refers to the outcome of the investigator's/designee's review of the subject's medical history for study eligibility, as obtained via a verbal interview with the subject or from the subject's medical records; or postmenopausal defined as 12 months of spontaneous amenorrhea. In questionable cases a blood sample with simultaneous follicle stimulating hormone (FSH) \>40 milliinternational units per/millilitre (MIU/mL) and estradiol \<40 picogram/millilitre (pg/mL) (\<147 picomoles 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, if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.; Child-bearing potential with negative pregnancy test as determined by serum or human chorionic gonadotropin (hCG) test at screening or urine hCG test prior to dosing AND ; Agrees to use one of the contraception methods for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Female subjects must agree to use contraception until the follow-up visit.; OR has only same-sex partners, when this is her preferred and usual lifestyle.
- •Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form
- •Subjects who are current non-smokers and who have a pack history of \<=10 pack years. A subject may not have used inhaled tobacco products within the past 3 months (i.e., cigarettes, cigars or pipe tobacco). \[number of pack years = (number of cigarettes per day / 20) x number of years smoked\].
- •Alanine transaminase (ALT), alkaline phosphatase and bilirubin \<= 1.5x Upper limit of normal (ULN) (isolated bilirubin \>1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin \<35%).
- •Based on single or averaged corrected QT interval (QTc) values of triplicate electrocardiogram (ECGs) obtained over a brief recording period: QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 milliseconds (msec); or QTcF \<480 msec in subjects with Bundle Branch Block.
- •Asthma therapy: Subjects must have been on their current therapy for at least eight weeks and a stable dose for four weeks prior to the screening visit:
Exclusion Criteria
- •Criteria Based Upon Medical Histories
- •Any clinically relevant medical condition or abnormality identified during the screening medical assessment and procedures, physical examination, or laboratory assessments (including clinical chemistry and haematology), which in the opinion of the Investigator and/or GSK Medical Monitor is likely to affect the safety of the subject and/or interfere with the study procedures and outcomes.
- •Acute exacerbation of asthma in the last 6 months prior to the Screening visit.
- •Subjects on treatment with fluticasone propionate either as monotherapy or in combination at a total daily dose higher than 500 mcg or budesonide monotherapy or in combination at a total daily dose higher than 800 mcg or beclomethasone (CFC) at a total daily dose higher than 1000 mcg or beclomethasone (HFA) at a total daily dose higher than 400mcg are excluded from the study
- •Subjects with other significant pulmonary diseases (pneumonia, pneumothorax, atelectasis, pulmonary fibrotic disease, bronchopulmonary dysplasia, chronic bronchitis, emphysema, chronic obstructive pulmonary disease, or other respiratory abnormalities other than asthma).
- •Use of oral/injectable/depot corticosteroid for any indication within 3 months prior to the Screening visit.
- •Use of any anti immunoglobulin E (Anti-IgE) (e.g. Xolair) in any period prior to screening.
- •Use of intra-nasal steroids (INS). To be eligible for the study, patients on INS therapy will be required to switch to non-INS therapy at screening
- •Current or chronic history of liver disease, or known hepatic or biliary abnormalities (with the exception of Gilbert's syndrome or asymptomatic gallstones).
- •History of regular alcohol consumption within 6 months of the study defined as: For Australian sites: An average weekly intake of \>21 units for males or \>14 units for females. One unit (= standard drink) is equivalent to 10 g of alcohol: 270 mL of full strength beer (4.8%), 375 mL of mid strength beer (3.5%), 470 mL of light beer (2.7%), 250 mL pre-mix full strength spirit (5%), 100 mL of wine (13.5%) and 30 mL of spirit (40%); For South African sites: An average weekly intake of \>21 units for males or \>14 units for females. One unit is equivalent to 8 grams (g) of alcohol: a half-pint (approximately 330 mL) of beer, 1 glass (125 mL) of wine or 1 (25 mL) measure of spirits.
Arms & Interventions
Sequence 1
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of A-B-B-A in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Fluticasone Propionate/Salmeterol Xinafoate DISKUS
Sequence 1
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of A-B-B-A in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Placebo to Match DISKUS
Sequence 1
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of A-B-B-A in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Fluticasone Propionate/Salmeterol Xinafoate ROTACAPS
Sequence 1
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of A-B-B-A in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Placebo to Match ROTACAPS
Sequence 2
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of B-A-A-B in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Fluticasone Propionate/Salmeterol Xinafoate DISKUS
Sequence 2
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of B-A-A-B in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Placebo to Match DISKUS
Sequence 2
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of B-A-A-B in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Fluticasone Propionate/Salmeterol Xinafoate ROTACAPS
Sequence 2
Subjects will receive FSC 100/50 mcg delivered via the Ddpi (Treatment A) and FSC 100/50 mcg delivered via the Rdpi (Treatment B) in the sequence of B-A-A-B in four treatment periods of 10 days each. Subjects will receive both active treatment and matching placebo at the same time from two separate devices twice daily. There will be no wash-out between treatment periods
Intervention: Placebo to Match ROTACAPS
Outcomes
Primary Outcomes
Salmeterol maximum observed concentration (Cmax)
Time Frame: Day 10 of each treatment period (pre-morning dose and at 5, 10, 30 minutes and 1, 2, 4, 8, 10 and 12 hours post- morning dose)
Salmeterol Cmax will be determined from the plasma salmeterol concentration-time data
Fluticasone propionate (FP) area under the concentration-time curve over the dosing interval (AUCtau)
Time Frame: Day 10 of each treatment period (pre-morning dose and at 5, 10, 30 minutes and 1, 2, 4, 8, 10 and 12 hours post- morning dose)
FP AUCtau will be determined from the plasma FP concentration-time data
Secondary Outcomes
- FP Cmax(Day 10 of each treatment period (pre-morning dose and at 5, 10, 30 minutes and 1, 2, 4, 8, 10 and 12 hours post- morning dose))
- Clinical laboratory safety assessments(Up to 12 weeks)
- Potassium and Glucose measurements(Up to 10 weeks)
- Weighted mean serum cortisol over 12 hours on the last day of each treatment period (Day 10)(Day 10 of each treatment period)
- Serum cortisol minimum observed concentration (Cmin)(Day 10 of each treatment period)
- Heart rate (HR) measurements(Up to 10 weeks)
- Blood pressure (BP) measurements(Up to 10 weeks)
- Salmeterol AUCtau(Day 10 of each treatment period (pre-morning dose and at 5, 10, 30 minutes and 1, 2, 4, 8, 10 and 12 hours post- morning dose))
- FP and salmeterol time to Cmax (Tmax)(Day 10 of each treatment period (pre-morning dose and at 5, 10, 30 minutes and 1, 2, 4, 8, 10 and 12 hours post- morning dose))
- Number of subjects with adverse events(Up to 12 weeks)