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.
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:
1. Subjects on fluticasone propionate/salmeterol combination 100/50 microgram (mcg)
treatment via a DISKUS inhaler prior to the study will be allowed to remain on
their treatment regimen until randomization provided all other eligibility
criteria are met.;
2. Subjects on treatment with fluticasone propionate/salmeterol combination 125/25
mcg via a metered dose inhaler will be required to switch to fluticasone
propionate/salmeterol combination 100/50 mcg via the GlaxoSmithkline
(GSK)-provided DISKUS inhaler for between 14 and 28 days prior to randomization;
3. Subjects on low dose inhaled corticosteriod (ICS) monotherapy (up to a total
daily dose of fluticasone propionate 250 total daily dose mcg or other ICS
equivalent e. g. budesonide up to 400 mcg total daily dose) will switch to
fluticasone propionate/salmeterol combination 100/50 mcg via the GSK-provided
DISKUS inhaler for between 14 and 28 days prior to randomization;
4. Subjects on medium dose ICS monotherapy ( greater than 250 and up to 500 mcg of
fluticasone propionate total daily dose or other ICS equivalent e. g. budesonide
greater than 400 mcg and up to 800 mcg total daily dose) will switch to
fluticasone propionate/salmeterol combination 100/50 mcg twice daily via the
GSK-provided DISKUS inhaler for 28 days prior to randomization;
5. Subjects on low dose Symbicort (any doses that are no greater than 400/12 mcg
total daily dose) will be switched to fluticasone propionate/salmeterol
combination 100/50 mcg via the GSK-provided DISKUS inhaler for between 14 and 28
days prior to randomization.
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.
- A known or suspected history of drug abuse within 12 months of the Screening visit.
- History of sensitivity to heparin or heparin-induced thrombocytopenia.
- History of sensitivity to salbutamol or any of the study medications, or components
thereof (including severe milk protein allergy) or a history of drug or other allergy
that, in the opinion of the investigator or GSK Medical Monitor, contraindicates
their participation.
Criteria Based Upon Diagnostic Assessments
- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening
- A positive pre-study drug screen.
- A positive test for Human Immunodeficiency Virus (HIV) antibody.
- Subjects with known abnormal levels of serum cortisol
- A subject will not be eligible if he/she has clinical visual evidence of oral
candidiasis prior to randomisation
- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.
- Lactating females.
- The subject has participated in a clinical trial and has received an investigational
product within the following time period prior to the first dosing day in the current
study: 30 days, 5 half-lives or twice the duration of the biological effect of the
investigational product (whichever is longer).
- Exposure to more than four new chemical entities within 12 months prior to the first
dosing day.
- Grapefruit or grapefruit juice containing products are excluded from 2 weeks prior to
randomisation until collection of the final blood sample at treatment period 4.
- Drugs that inhibit the cytochrome P450 isoform, 3A4 (CYP3A4), are excluded from 2
weeks prior to randomisation until collection of the final blood sample at treatment
period 4. CYP3A4 inhibitors include cimetidine, clarithromycin, erythromycin,
ciprofloxacin, ritonavir, ketoconazole, and azole antifungals.
- Use of prescription or non-prescription drugs, vitamins, herbal and dietary
supplements, within seven days or 5 half-lives (whichever is longer) prior to the
first dose of study medication, which in the opinion of the Principal Investigator,
may interfere with study outcome. Specifically, calcium and vitamin D supplements
and bisphosphonates are not allowed throughout the study.
- Subjects, who, in the opinion of the Investigator, are not able to comply with the
protocol requirements.
