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

• Status: Completed
• Trial end date: 2012-09-04
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1
• Accepts Healthy Volunteers?: Accepts Healthy Volunteers

Details

• Lead Sponsor: GlaxoSmithKline
• Treatments: Fluticasone; Fluticasone Propionate, Salmeterol Xinafoate Drug Combination; Fluticasone-Salmeterol Drug Combination; Salmeterol Xinafoate

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.