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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/show/NCT01540708




Registration number
NCT01540708
Ethics application status
Date submitted
23/02/2012
Date registered
29/02/2012
Date last updated
19/06/2018

Titles & IDs
Public title
A Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation and ROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol
Scientific title
An Open-label, Randomised, Cross-over, Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation andROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol.
Secondary ID [1] 0 0
116409
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Asthma 0 0
Condition category
Condition code
Respiratory 0 0 0 0
Asthma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - SERETIDE Rotacaps
Treatment: Drugs - SERETIDE Diskus

Experimental: SERETIDE Rotacaps - Fluticasone propionate/Salmeterol combination administered at 2 doses (250/50 mcg and 100/50 mcg) and delivered in a capsule-based inhaler (Rotahaler). Devices with varying airflow resistance, low, intermediate and high, will be used.

Active Comparator: SERETIDE Diskus - Fluticasone propionate/Salmeterol combination administered at 2 doses (250/50 mcg and 100/50 mcg) and delivered in a multi-dose dry powder inhaler


Treatment: Drugs: SERETIDE Rotacaps
The study will be conducted in 3 parts with an adaptive design where pharmacokinetic data analysis follows each part to enable a decision on whether progression to the subsequent parts is required. Thirty six subjects will be enrolled in each part. Part A will test an alternative version of the Rotahaler with a lower airflow resistance. The study will then test one or more of the following options depending on the outcome of part A. If progressed, part B will test modified Rotacap formulations including: (1) modified blend formulation, (2) reduced capsule fill weights, (3) different capsule types. Part B will also test other versions of the Rotahaler with intermediate airflow resistance. Part C will test the lower strength FP/salmeterol (100/50 mcg or lower) and/or a new unit dose DPI device (BUDI). In each arm, subjects will be administered 7 doses (3.5 days bid) with PK sampling following administration of the 7th dose on the morning of Day 4.

Treatment: Drugs: SERETIDE Diskus
The study will be conducted in 3 parts with an adaptive design where pharmacokinetic data analysis follows each part to enable a decision on whether progression to the subsequent parts is required. Thirty six subjects will be enrolled in each part. Part A will test an alternative version of the Rotahaler with a lower airflow resistance. The study will then test one or more of the following options depending on the outcome of part A. If progressed, part B will test modified Rotacap formulations including: (1) modified blend formulation, (2) reduced capsule fill weights, (3) different capsule types. Part B will also test other versions of the Rotahaler with intermediate airflow resistance. Part C will test the lower strength FP/salmeterol (100/50 mcg or lower) and/or a new unit dose DPI device (BUDI). In each arm, subjects will be administered 7 doses (3.5 days bid) with PK sampling following administration of the 7th dose on the morning of Day 4.

Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Selection of a device and formulation combination of fluticasone propionate/salmeterol (250/50mcg or lower) which has pharmacokinetic equivalence (ratio 0.8 to 1.25) to fluticasone propionate/salmeterol (250/50mcg) delivered via the Ddpi
Timepoint [1] 0 0
PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose
Primary outcome [2] 0 0
Comparison of he pharmacokinetic parameters of fluticasone propionate/salmeterol (250/50mcg or lower) delivered from a range of devices and/or formulations to those of fluticasone propionate/salmeterol (250/50mcg) delivered via the Ddpi - Area under the plasma fluticasone propionate concentration-time curve over dosing interval; maximum concentration for fluticasone propionate and salmeterol plasma concentration-time curve on the last day of each study treatment period (Day 4).
Timepoint [2] 0 0
PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose
Secondary outcome [1] 0 0
Determination of the pharmacokinetic equivalence of the selected device/formulation combination of fluticasone propionate/salmeterol administered at a lower dose to match fluticasone propionate/salmeterol administered at 100/50mcg dose from Ddpi - Pharmacokinetic parameters: time of maximum observed concentration;terminal phase rate constant; terminal phase half-life for fluticasone propionate and salmeterol) on the last day of each treatment period (Day 4).
Timepoint [1] 0 0
PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose
Secondary outcome [2] 0 0
Assessment of the PK characteristics of the BUDI inhaler containing 100/50mcg fluticasone propionate/salmeterol and 250/50mcg fluticasone propionate/salmeterol - Pharmacokinetic parameters: time of maximum observed concentration;terminal phase rate constant; terminal phase half-life for fluticasone propionate and salmeterol) on the last day of each treatment period (Day 4).
Timepoint [2] 0 0
PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose

Eligibility
Key inclusion criteria
INCLUSION CRITERIA:

A subject will be eligible for inclusion in this study only if all of the following
criteria apply:

- ALT, alkaline phosphatase and bilirubin less than or equal to 1.5xULN (isolated
bilirubin >1.5xULN is acceptable if bilirubin is fractionated and direct bilirubin
<35%).

- Single QTc, QTcB or QTcF < 450 msec; or QTc < 480 msec in subjects with Bundle Branch
Block.

- Healthy as determined by a responsible and experienced physician, based on a medical
evaluation including medical history, physical examination, laboratory tests and
cardiac monitoring. A subject with a clinical abnormality or laboratory parameters
outside the reference range for the population being studied may be included only if
the Investigator and the GSK Medical Monitor agree that the finding is unlikely to
introduce additional risk factors and will not interfere with the study procedures.

- Male or female between 18 and 65 years of age inclusive, at the time of signing the
informed consent.

- 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; or postmenopausal defined as 12 months of spontaneous
amenorrhea [in questionable cases a blood sample with simultaneous follicle
stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 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 protocol approved 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 should 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 and is abstinent or agrees to use one of the protocol approved
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

- Capable of giving informed consent, which includes compliance with the study
requirements and restrictions listed in the consent form.

- BMI within the range 18 and 35 kg/m2 (inclusive).

- Able to use the inhaler devices adequately after training

EXCLUSION CRITERIA:

A subject will not be eligible for inclusion in this study if any of the following criteria
apply:

Medical Condition
Minimum age
18 Years
Maximum age
65 Years
Gender
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Exclusions:

- Subjects who have a current diagnosis or a history of asthma, excluding childhood
asthma which has been discharged by physician (e.g., for any FTIH where risk of
bronchoconstriction is unknown, or compound specific where risk of
bronchoconstriction). This must be documented in the subject's medical notes.

- Subjects who have a current and previous diagnosis of COPD. This must be documented in
the subject's medical notes.

- Current or chronic history of liver disease, or known hepatic or biliary abnormalities
(with the exception of Gilbert's syndrome or asymptomatic gallstones).

- A positive pre-study Hepatitis B surface antigen or positive Hepatitis C antibody
result within 3 months of screening

- A positive test for HIV antibody.

- Pregnant females as determined by positive serum hCG test at screening or prior to
dosing.

- Lactating females.

- Subject is mentally or legally incapacitated.

- Unwillingness or inability to follow the procedures outlined in the protocol.

Medical Exclusions:

- 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 5 half-lives (whichever is
longer) prior to the first dose of study medication, unless in the opinion of the
Investigator and GSK Medical Monitor the medication will not interfere with the study
procedures or compromise subject safety.

- 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.

- History of sensitivity to any of the study medications, or components thereof or a
history of drug or other allergy that, in the opinion of the investigator or GSK
Medical Monitor, contraindicates their participation.

- History of sensitivity to heparin or heparin-induced thrombocytopenia.

Lifestyle Exclusions:

- A positive pre-study drug/alcohol screen. A minimum list of drugs that will be
screened for include amphetamines, barbiturates, cocaine, opiates, cannabinoids and
benzodiazepines.

- History of regular alcohol consumption within 6 months of the screening visit defined
by the following Australian guidelines as:

Males: An average weekly intake greater than 21 units or an average daily intake greater
than 3 units. Females: An average weekly intake greater than 14 units or an average daily
intake greater than 2 units.

One unit is equivalent to 270 mL of full strength beer, 470 mL of light beer, 30 mL of
spirits and 100 mL of wine.

- Grapefruit, pummelos, or grapefruit juice containing products are excluded from 2
weeks prior to randomisation (all study parts) until collection of the final blood
sample on Day 4.

- Where participation in the study would result in donation of blood or blood products
in excess of 500 mL within a 56 day period.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint(s)
Statistical methods / analysis

Recruitment
Recruitment status
Completed
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 0 0
GSK Investigational Site - Randwick
Recruitment postcode(s) [1] 0 0
2031 - Randwick

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
GlaxoSmithKline
Address
Country

Ethics approval
Ethics application status

Summary
Brief summary
The purpose of this study is to optimise the device and/or formulation of the Fluticasone
propionate (FP)/salmeterol (SALM) unit dose powder inhaler (Rotahaler) to achieve drug
delivery characteristics comparable to the Fluticasone propionate /salmeterol DISKUS inhaler.
The indication is asthma and chronic obstructive pulmonary disease. The study is an
open-label, randomised, cross-over, single centre study in healthy volunteers and will be
conducted in a maximum of 3 parts, A, B and C. The design is adaptive and pharmacokinetic
(PK) data analysis follows each part to enable a decision on whether progression to the
subsequent parts is required.

Part A of the study will test an alternative version of the Rotahaler with a low airflow
resistance. The study will then test one or more of the following options depending on the
outcome of part A. If progressed, part B will test modified Rotacap formulations including:
(1) modified blend formulation, (2) reduced capsule fill weights, (3) different capsule
types. Part B will also test other versions of the Rotahaler with intermediate airflow
resistance. Part C will test the lower strength FP/salmeterol (100/50 mcg or lower) and/or a
new unit dose DPI device (BUDI).

A total of 36 subjects will be enrolled in each part to ensure 32 complete. In each
cross-over arm, subjects will be administered 7 doses (3.5 days bid) with PK sampling
following administration of the 7th dose. A three-day minimum wash-out period will separate
each cross-over arm.
Trial website
https://clinicaltrials.gov/show/NCT01540708
Trial related presentations / publications
Calverley PM, Anderson JA, Celli B, Ferguson GT, Jenkins C, Jones PW, Yates JC, Vestbo J; TORCH investigators. Salmeterol and fluticasone propionate and survival in chronic obstructive pulmonary disease. N Engl J Med. 2007 Feb 22;356(8):775-89.
Celli BR, MacNee W; ATS/ERS Task Force. Standards for the diagnosis and treatment of patients with COPD: a summary of the ATS/ERS position paper. Eur Respir J. 2004 Jun;23(6):932-46. Erratum in: Eur Respir J. 2006 Jan;27(1):242.
Ferguson GT, Anzueto A, Fei R, Emmett A, Knobil K, Kalberg C. Effect of fluticasone propionate/salmeterol (250/50 microg) or salmeterol (50 microg) on COPD exacerbations. Respir Med. 2008 Aug;102(8):1099-108. doi: 10.1016/j.rmed.2008.04.019. Epub 2008 Jul 9.
GINA: Global strategy for asthma management and prevention. NHLBI/WHO/GARD, Washingon DC 2006-updated 2009.
GlaxoSmithKline Document Number RM2007/00413/03. CCI18781+GR33343 Investigator's Brochure, version number 12, dated 4 May 2011.
GlaxoSmithKline document number YM2010/00082/02 Study ASR114334: A comparative bioavailability study to compare the pharmacokinetics and pharmacodynamic effects of Fluticasone propionate and Salmeterol delivered by Fluticasone propionate/ Salmeterol combination in a capsule-based inhaler and a multi-dose dry powder inhaler, in patients with moderate asthma and patients with moderate to severe COPD.
Fabbri L, Pauwels RA, Hurd SS; GOLD Scientific Committee. Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease: GOLD Executive Summary updated 2003. COPD. 2004 Apr;1(1):105-41; discussion 103-4.
James LP, Letzig L, Simpson PM, Capparelli E, Roberts DW, Hinson JA, Davern TJ, Lee WM. Pharmacokinetics of acetaminophen-protein adducts in adults with acetaminophen overdose and acute liver failure. Drug Metab Dispos. 2009 Aug;37(8):1779-84. doi: 10.1124/dmd.108.026195. Epub 2009 May 13.
Kardos P, Wencker M, Glaab T, Vogelmeier C. Impact of salmeterol/fluticasone propionate versus salmeterol on exacerbations in severe chronic obstructive pulmonary disease. Am J Respir Crit Care Med. 2007 Jan 15;175(2):144-9. Epub 2006 Oct 19.
Schuirmann DJ. A comparison of the two one-sided tests procedure and the power approach for assessing the equivalence of average bioavailability. J Pharmacokinet Biopharm. 1987 Dec;15(6):657-80.
Public notes

Contacts
Principal investigator
Name 0 0
GSK Clinical Trials
Address 0 0
GlaxoSmithKline
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries

Summary results
Other publications