A Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation and ROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol

This study has been completed.
Sponsor:
Information provided by (Responsible Party):
GlaxoSmithKline
ClinicalTrials.gov Identifier:
NCT01540708
First received: February 23, 2012
Last updated: April 11, 2013
Last verified: April 2013
  Purpose

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.


Condition Intervention Phase
Asthma
Drug: SERETIDE Rotacaps
Drug: SERETIDE Diskus
Phase 1

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Bio-equivalence Study
Intervention Model: Crossover Assignment
Masking: Open Label
Primary Purpose: Treatment
Official 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.

Resource links provided by NLM:


Further study details as provided by GlaxoSmithKline:

Primary Outcome Measures:
  • 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 [ Time Frame: PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose ] [ Designated as safety issue: No ]
  • 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 [ Time Frame: PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose ] [ Designated as safety issue: No ]
    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).


Secondary Outcome Measures:
  • 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 [ Time Frame: PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose ] [ Designated as safety issue: No ]
    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).

  • Assessment of the PK characteristics of the BUDI inhaler containing 100/50mcg fluticasone propionate/salmeterol and 250/50mcg fluticasone propionate/salmeterol [ Time Frame: PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose ] [ Designated as safety issue: No ]
    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).


Enrollment: 36
Study Start Date: January 2012
Study Completion Date: September 2012
Primary Completion Date: September 2012 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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.
Drug: 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.
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
Drug: 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.

  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years to 65 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   Yes
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 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.
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01540708

Sponsors and Collaborators
GlaxoSmithKline
Investigators
Study Director: GSK Clinical Trials GlaxoSmithKline
  More Information

Publications:
GOLD 2006 Global Strategy for the Diagnosis, Management, and Prevention of Chronic Obstructive Pulmonary Disease (2006)-updated 2009.

Responsible Party: GlaxoSmithKline
ClinicalTrials.gov Identifier: NCT01540708     History of Changes
Other Study ID Numbers: 116409
Study First Received: February 23, 2012
Last Updated: April 11, 2013
Health Authority: Australia: Department of Health and Ageing Therapeutic Goods Adminstration
United States: Food and Drug Administration

Keywords provided by GlaxoSmithKline:
Asthma
Respiratory
COPD

Additional relevant MeSH terms:
Asthma
Bronchial Diseases
Respiratory Tract Diseases
Lung Diseases, Obstructive
Lung Diseases
Respiratory Hypersensitivity
Hypersensitivity, Immediate
Hypersensitivity
Immune System Diseases
Salmeterol
Fluticasone
Fluticasone, salmeterol drug combination
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Pharmacologic Actions
Anti-Asthmatic Agents
Respiratory System Agents
Therapeutic Uses
Adrenergic beta-2 Receptor Agonists
Adrenergic beta-Agonists
Adrenergic Agonists
Adrenergic Agents
Neurotransmitter Agents
Molecular Mechanisms of Pharmacological Action
Anti-Inflammatory Agents
Dermatologic Agents
Anti-Allergic Agents
Glucocorticoids

ClinicalTrials.gov processed this record on September 14, 2014