GSK Clincal Study Register

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1 In February 2013, GlaxoSmithKline (GSK) announced a commitment to further clinical transparency through the public disclosure of GSK Clinical Study Reports (CSRs) on the GSK Clinical Study Register. The following guiding principles have been applied to the disclosure: Information will be excluded in order to protect the privacy of patients and all named persons associated with the study Patient data listings will be completely removed* to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register. Aggregate data will be included; with any direct reference to individual patients excluded *Complete removal of patient data listings may mean that page numbers are no longer consecutively numbered

2 CONFIDENTIAL CONFIDENTIAL The GlaxoSmithKline group group of companies of companies Division: World Wide Development Retention Category: GRS019 Information Type: Synopsis Clinical Pharmacology Study Report Title: Phase: Compound Number: A two-arm pilot study to assess the concentration of inhaled fluticasone propionate and budesonide in plasma and adipose tissue after chronic dosing in patients with asthma and after acute and repeat dosing in healthy subjects. I CCI18781 Effective Date: 20-August-2007 Description: This was a two-arm pilot study designed to assess the concentration of inhaled fluticasone propionate and budesonide in plasma and adipose tissue after chronic dosing in patients with asthma and after acute and repeat dosing in healthy subjects. However, only three subjects taking fluticasone propionate were recruited as the study was terminated early due to the inability to develop a reproducible, validated analytical method for budesonide and budesonide esters in adipose tissue. Only a few samples were therefore available for plasma and adipose pharmacokinetic analysis. Fluticasone propionate was well tolerated by subjects with asthma at doses of up to 1000 µg/day. Subject: Budesonide, fluticasone propionate, adipose tissue Authors: Initiation Date: 13 August 2004 Completion Date: 08 October 2004 Date of Report: 20 August 2007 Sponsor Signatory: (and Medical Officer) MD, MSc, FFPM Vice President Respiratory Diseases and Inflammation Clinical Pharmacology and Discovery Medicine This study was performed in compliance with Good Clinical Practices including the archiving of essential documents. Copyright 2007 the GlaxoSmithKline group of companies. All rights reserved. Unauthorised copying or use of this information is prohibited. 1 1

3 CONFIDENTIAL TABLE OF CONTENTS Page ABBREVIATIONS SYNOPSIS OTHER DATA SOURCE TABLES

4 CONFIDENTIAL CONFIDENTIAL Abbreviations AE ECG SAE Adverse event Electrocardiography Serious adverse event Trademark Information Trademarks of the GlaxoSmithKline group of companies DISKUS FLIXOTIDE SERETIDE Trademarks not owned by the GlaxoSmithKline group of companies Pulmicort Symbicort Turbuhaler 3 2

5 CONFIDENTIAL CONFIDENTIAL SYNOPSIS Identifier: Study Number: Title A two-arm pilot study to assess the concentration of inhaled fluticasone propionate and budesonide in plasma and adipose tissue after chronic dosing in patients with asthma and after acute and repeat dosing in healthy subjects. Investigator Dr. Study Centre UK. Publications None at the time of this report. Study Period 13 August October Phase of Development I Objectives Primary To compare the trough concentrations (normalised by dose) of fluticasone propionate and budesonide in adipose tissue at steady state in asthmatic patients. 4 3

6 CONFIDENTIAL CONFIDENTIAL Secondary Part A To obtain the ratio of the trough concentration of fluticasone propionate in adipose tissue to trough concentration of fluticasone propionate in plasma at steady state in asthmatic patients. To obtain the ratio of the trough concentration of budesonide in adipose tissue to trough concentration of budesonide in plasma at steady state in asthmatic patients. To characterise the peak and trough concentrations of fluticasone propionate in plasma at steady state in asthmatic patients. To characterise the peak and trough concentrations of budesonide in plasma at steady state in asthmatic patients Part B To characterise the time-course of adipose concentrations of fluticasone propionate in healthy subjects after multiple dosing. To characterise the time-course of plasma concentrations of fluticasone propionate in healthy subjects after multiple dosing. To characterise the time-course of adipose concentrations of budesonide in healthy subjects after multiple dosing. To characterise the time-course of plasma concentrations of budesonide in healthy subjects after multiple dosing. Endpoints Primary Mean and 90% confidence intervals for trough concentrations (normalised by dose) of fluticasone propionate and budesonide in adipose tissue at steady state in asthmatic patients. Secondary Part A The ratio of the trough concentration of fluticasone propionate in adipose tissue to trough concentration of fluticasone propionate in plasma at steady state in asthmatic patients. The ratio of the trough concentration of budesonide in adipose tissue to trough concentration of budesonide in plasma at steady state in asthmatic patients. The trough and peak concentrations of fluticasone propionate in plasma at steady state in asthmatic patients. 5 4

7 CONFIDENTIAL The trough and peak concentrations of budesonide in plasma at steady state in asthmatic patients. Part B The trough concentrations of fluticasone propionate in adipose tissue before, during and after steady state in healthy subjects. The trough concentrations of budesonide in adipose tissue before, during and after steady state in healthy subjects. The peak and trough concentrations of fluticasone propionate in plasma before, during and after steady state in healthy subjects. The peak and trough concentrations of budesonide in plasma before, during and after steady state in healthy subjects. To determine the parameters relating to entry of drug from plasma to adipose tissues. These include plasma-fat tissue partition coefficient and distribution rate constant in adipose tissues for fluticasone propionate and budesonide. Methodology Part A CONFIDENTIAL Patients with asthma (n=24) were to be recruited with respect to their asthma medication as follows: Twelve patients who were already using budesonide or Symbicort by inhalation at budesonide doses of 200 to 400 µg twice-daily. At least six of these subjects were to be taking the high daily dose (800 µg). Twelve patients who were already using fluticasone propionate (or SERETIDE ) by inhalation at fluticasone propionate doses 200 to 500 µg twice-daily. At least six of these subjects were to be taking the high daily dose (800 to 1000 µg). These 24 patients were to be recruited into two groups as follows: Group A-1: six patients: three patients on budesonide alone or Symbicort (400 µg twice-daily) and three patients on fluticasone propionate alone or SERETIDE (400 to 500 µg twice-daily). Group A-2: Up to 18 patients. These patients were only to be recruited if the results from the assessment of drug concentrations from Group A-1 indicated that detectable concentrations would be achieved in Group A-2 and Part B. The 18 patients recruited into Group A-2 were only to be recruited if the results from the assay to measure fluticasone propionate and budesonide concentrations performed on the adipose and plasma samples collected from subjects in Group A-1 were satisfactory. 6 5

8 CONFIDENTIAL All 24 patients were required to participate in the following visits during Part A of the study regardless of whether they were recruited into Group A-1 or A-2: Screening visit up to 6 weeks prior to Visit 1 to establish clinical stability and suitability for adipose biopsy. Run-in period for 2 weeks prior to Visit 1. Patients were asked to keep a diary to record the administration of their medication over 2 weeks. Visit 1 biopsy at trough; plasma samples at peak and trough. Follow-up visit 5 to 14 days after the biopsy taken at Visit 1 (to inspect biopsy site). Part B CONFIDENTIAL This was an open-label, randomised, parallel group, repeat-dose part in 21 healthy subjects. Each subject was to be administered concomitant doses of fluticasone propionate (400 µg twice-daily) and budesonide (400 µg twice-daily) inhaled via DISKUS and Turbuhaler, respectively. Subjects were to be randomised into one of two parallel groups: Group B-1 and Group B-2. These two groups differed with regard to the length of time the subjects received the investigational product (up to a maximum of 7 days) and when the two biopsies were performed during the study period. Group B-1 was to include 13 subjects who were randomly assigned to 1 7 days dosing and participated in the following study visits: Screening Visit Treatment Period (1 7 days) Visit 1 (Day 1) Visit 2 (days 1 7) Visit 3 (days 1 7) Follow-up visit Up to 6 weeks prior to study start (to establish eligibility for adipose biopsy). First dose + plasma samples (peak and trough). First biopsy (trough) + plasma samples (peak and trough). Second biopsy (trough) + plasma samples (peak and trough). Subjects administered a morning dose but no evening dose. 5 to 14 days after Visit 3 to inspect biopsy site. All biopsies were to be taken at the trough time-point, which for this study was within 1 h prior to the morning dose on Visits 2 and

9 CONFIDENTIAL CONFIDENTIAL Group B-2 was to include eight subjects who received 7 days dosing and participated in the following study visits: Screening Visit Treatment Period (1 9 days) Visit 1 (Day 1) Visit 2 (Day 7) Visit 3 (days 7 9) Follow-up visit Up to 6 weeks prior to study start (to establish eligibility for adipose biopsy). First dose + plasma samples (peak and trough). First biopsy (peak) + serial plasma samples for pharmacokinetic profile). All subjects administered a morning dose only. Second biopsy + plasma samples (peak [Day 7 only] and trough). Subjects administered a morning dose but no evening dose. (Peak biopsies taken if Visit 3 occurred on Day 7. Trough biopsies taken if Visit 3 occurred on days 8 or 9.) 5 to 14 days after Visit 3 to inspect biopsy site. Number of Subjects Number of Subjects Planned, N 45 Randomised, N 3 Completed, n (%) 3 (100) Total Withdrawn (any reason), n (%) 0 Withdrawn due to Adverse Events, n (%) 0 Withdrawn due to Other Reason, n (%) 0 Source Data: Table 15.1 Only three subjects taking fluticasone propionate were recruited to the study since it was terminated early due to the inability to develop a reproducible validated analytical method for budesonide and budesonide esters in adipose tissue. Diagnosis and Main Criteria for Inclusion Subjects were eligible for this study if they were non-smoking males or females, aged 18 to 60 years inclusive. Women were eligible to enter the study if they were not pregnant or nursing, were of non-childbearing potential, or were of childbearing potential and using an appropriate method of contraception with a documented failure rate of less than 1% per year for the duration of the study and for 1 month after the last administration of investigational products. In addition, asthmatic patients had to have clinically stable, medically diagnosed asthma that was treated with inhaled fluticasone propionate (400 to 1000 µg daily, alone or as SERETIDE) or budesonide (400 to 800 µg daily, alone or as Symbicort) and had been treated with the same dose for at least 3 months prior to screening. 8 7

10 CONFIDENTIAL Subjects with a clinical exacerbation of asthma within 3 months of screening or who had received treatment with oral corticosteroids within 2 months of the screening visit were not eligible. Treatment Administration Part A During Part A of the study, the asthmatic patients were to continue using their own supply of fluticasone propionate (or SERETIDE) at doses of 200 to 500 µg twice-daily or budesonide (or Symbicort) at doses of 200 to 400 µg twice-daily, according to their usual routine. Part B For Part B of the study fluticasone propionate (100 µg per actuation) was supplied as FLIXOTIDE and was supplied pre-packed into DISKUS inhalers by the study site. Budesonide (400 µg per actuation) was supplied as Pulmicort and was supplied prepacked into Turbuhaler inhalers by the study site. The healthy subjects inhaled fluticasone propionate via the DISKUS inhaler. As fluticasone propionate was administered at 100 µg per actuation subjects had to administer four actuations in the morning and another four actuations in the evening to receive a total dose of 800 µg per day. The subjects inhaled budesonide via the Turbuhaler inhaler at 400 µg per actuation. Therefore subjects were required to administer one actuation of budesonide (400 µg) in the morning and another actuation (400 µg) in the evening to receive a total dose of 800 µg per day. Criteria for Evaluation Safety: Adverse events (AEs), serious adverse events (SAEs), 12-lead electrocardiography (ECG), vital signs, clinical laboratory evaluations and forced expiratory volume in 1 second measurements. Pharmacokinetics: Parts A and B: Determination of fluticasone propionate or budesonide concentration; fat biopsy samples. Statistical Methods CONFIDENTIAL No analyses were performed due to the paucity of data. 9 8

11 CONFIDENTIAL CONFIDENTIAL Summary Demographics The demographic characteristics of the subjects in this study are presented in Table 1. All three subjects were asthmatic. Table 1 Demographic Characteristics N=3 Age, years Mean (range) 47 (30 57) Sex, n (%) Female: 2 (67) Male: 1 (33) Race, n(%) White 3 (100) Height, cm Mean (range) 168 ( ) Weight, kg Mean (range) 93.9 ( ) Body mass index, kg/m 2 Mean (range) 33.1 ( ) Source Data: Table 15.1 Pharmacokinetics Pharmacokinetic analyses were performed on only a limited number of samples. The raw data are presented in Table 2. Samples of adipose tissue for fluticasone propionate analysis were collected to reflect steady state trough fluticasone propionate levels and prior to dosing. 10 9

12 CONFIDENTIAL CONFIDENTIAL Table 2 Fluticasone Propionate Concentrations in Fat and Plasma 1. Safety Two subjects reported AEs during the study (Table 15.3). Neither AE was judged to be related to investigational product. No SAEs were reported during the study. This AE resolved. This AE was ongoing. All subjects had normal ECGs and vital signs at screening (Table 15.4 and Table 15.5). There were no ECG or vital sign values of potential clinical concern during the study (Table 15.6 and Table 15.7). No subject had treatment-emergent (i.e., not present at screening) clinical laboratory data (clinical chemistry, haematology and urinalysis) of potential clinical concern (Table 15.8). Conclusions Fluticasone propionate was well tolerated by subjects with asthma at doses of up to 1000 µg/day. Date of report August

13 CONFIDENTIAL OTHER DATA SOURCE TABLES Page Table 15.1 Demographic Data Table 15.2 Dosing Information by Treatment and Subject Table 15.3 Summary of Adverse Events Table 15.4 Screening Electrocardiographic Data by Subject Table 15.5 Screening Vital Signs Table 15.6 Subjects Who Had 12 Lead Electrocardiagraphic Findings of Potential Clinical Concern Table 15.7 Subjects Who Had Vital Signs of Potential Clinical Concern Table 15.8 Clinical Laboratory Data by Subject

14 This section contained data from each individual patient, rather than in aggregate. They have been excluded to protect patient privacy. Anonymized data from each patient may be made available subject to an approved research proposal. For further information please see the Patient Level Data section of the GSK Clincal Study Register.

15

16 SPONSOR INFORMATION PAGE Title: Study Identifier: A two-arm pilot study to assess the concentration of inhaled fluticasone propionate and budesonide in plasma and adipose tissue after chronic dosing in patients with asthma and after acute and repeat dosing in healthy subjects GlaxoSmithKline Greenford Road Greenford, Middlesex, UB6 0HE, UK Telephone: Sponsor Contact Information: Clinical Pharmacology GlaxoSmithKline Greenford Road Greenford Middlesex, UB6 0HE Sponsor Physician Contact Details: If there are any urgent queries concerning this study, or if any adverse events need to be reported immediately, the Physician Responsible (Dr may be contacted by telephoning: Greenford: Mobile: Outside normal business hours (08:00 16:00), or in the failure to contact the relevant person, ring Security Control Room at GlaxoSmithKline Research and Development on who will contact someone on your behalf. 2

17 INVESTIGATOR PROTOCOL AGREEMENT PAGE I agree: To assume responsibility for the proper conduct of the study at this site. To conduct the study in compliance with this protocol, any future amendments, and with any other study conduct procedures provided by GlaxoSmithKline (GSK). Not to implement any changes to the protocol without agreement from the sponsor and prior review and written approval from the Institutional Review Board (IRB) or Independent Ethics Committee (IEC), except where necessary to eliminate an immediate hazard to the subjects, or for administrative aspects of the study (where permitted by all applicable regulatory requirements). That I am thoroughly familiar with the appropriate use of the investigational product(s), as described in this protocol, and any other information provided by the sponsor including, but not limited to, the following: the current Clinical Investigator s Brochure / Investigator s Brochure (CIB/IB) or equivalent document, CIB/IB supplement (if applicable), and approved product label (if the product is marketed in this country and the label is not already provided as an equivalent to a CIB/IB). That I am aware of, and will comply with, good clinical practices (GCP) and all applicable regulatory requirements. To ensure that all persons assisting me with the study are adequately informed about the GSK investigational product(s) and of their study-related duties and functions as described in the protocol. Investigator Name: Investigator Signature Date 3

18 TABLE OF CONTENTS Page ABBREVIATIONS PROTOCOL SUMMARY INTRODUCTION Background Pharmacogenetics Rationale OBJECTIVE(S) Primary Secondary ENDPOINT(S) Primary Secondary STUDY DESIGN Study Design for Part A Study Design for Part B Group B Group B STUDY POPULATION Number of Subjects Eligibility Criteria Inclusion Criteria Exclusion Criteria Other Eligibility Criteria Considerations STUDY ASSESSMENTS AND PROCEDURES Demographic and Baseline Assessments Safety Lead ECG Procedures Vital Signs Clinical Laboratory Investigations FEV1 Measurements Pregnancy Pharmacokinetics Part A

19 Part B Pharmacogenetics INVESTIGATIONAL PRODUCT(S) Description of Investigational products Dosage and Administration Dose Rationale Asthmatic Patients Healthy Subjects Blinding Treatment Assignment Packaging and Labeling Preparation Handling and Storage Product Accountability Assessment of Compliance Treatment of Investigational Product Overdose Fluticasone propionate Budesonide Occupational Safety CONCOMITANT MEDICATIONS AND NON-DRUG THERAPIES Permitted and Prohibited Medications Non-Drug Therapies SUBJECT COMPLETION AND WITHDRAWAL Subject Completion Subject Withdrawal Subject Withdrawal from Study Subject Withdrawal from Investigational Product Screen and Baseline Failures ADVERSE EVENTS (AE) AND SERIOUS ADVERSE EVENTS (SAE) Definition of an AE Definition of a SAE Clinical Laboratory Abnormalities and Other Abnormal Assessments as AEs and SAEs Time Period, Frequency, and Method of Detecting AEs and SAEs Recording of AEs and SAEs Evaluating AEs and SAEs Assessment of Intensity

20 Assessment of Causality Follow-up of AEs and SAEs Prompt Reporting of SAEs to GSK Timeframes for Submitting SAE Reports to GSK Completion and Transmission of the SAE Reports Regulatory Reporting Requirements For SAEs Post-study AEs and SAEs SAEs Related to Study Participation DATA ANALYSIS AND STATISTICAL CONSIDERATIONS Hypotheses Treatment Comparisons of Interest Primary Comparisons of Interest Other Comparisons of Interest Interim Analysis Sample Size Considerations Sample Size Re-estimation Analysis Populations General Considerations for Data Analysis Withdrawal Derived and Transformed Data Assessment Windows Safety Analyses Extent of Exposure Adverse Events Clinical Laboratory Evaluations Other Safety Measures Clinical Pharmacology Data Analyses Pharmacokinetic Analyses Pharmacogenetics Analyses STUDY ADMINISTRATION Regulatory and Ethical Considerations Regulatory Authority Approval Ethical Conduct of the Study and Ethics Approval Informed Consent Investigator Reporting Requirements Study Monitoring Quality Assurance

21 12.4. Study and Site Closure Records Retention Provision of Study Results and Information to Investigators Data Management Confidentiality of Subject s PGx Data REFERENCES APPENDICES Appendix 1: Time and Events Table for Part A Appendix 2: Study Schematic Diagram Appendix 3: Country Specific Requirements

22 ABBREVIATIONS AE AUC BDS BID BQL BUD CBP CI CIB Cmax CPK CPK M&S CRF DNA ECG EDTA EISR FEV FP FSH FVC GCP GSK HPA HVT IB IEC IRB IUD Kp Kt L MedDRA mg ml MSDS PGx PIMS PK QC RAP SAE SNP Tmax t 1/2 Adverse Event Area Under the Curve Biomedical Data Sciences Twice daily Below Quantification Limit Budesonide Child bearing potential Confidence Interval Clinical Investigator Brochure Maximum concentration Clinical Pharmacokinetics Clinical Pharmacokinetics Modelling and Simulation Case Report Form Deoxyribonucleic Acid Electrocardiogram Ethylene Diamine Tetraacetic Acid Expedited Investigator Safety Reports Forced Expiratory Volume Fluticasone Propionate Follicle Stimulating Hormone Forced Volume Capacity Good Clinical Practice GlaxoSmithKline Hypopthalamic-Pituitary Adrenal Healthy Volunteer Investigator Brochure Independent Ethics Committee Institutional Review Board Intra Uterine Device Plasma-fat tissue partition coefficient Distribution rate constant Litres Medicinal Dictionary for Regulatory Activities milligrams Millilitres Materials Safety Data Sheet Pharmacogenetics Phase I Management System Pharmacokinetics Quality Control Reporting and Analysis Plan Serious Adverse Event Single Nucleotide Polymorphism Time of maximum concentration Half-life 8

23 PROTOCOL SUMMARY Rationale It has been suggested that fluticasone propionate (FP), being highly lipophilic, partitions into tissues and therefore, despite its low plasma levels, may result in tissue accumulation and a higher total systemic load than less lipophilic inhaled steroids [Clark, 1997; Källén, 2003]. Thus, FP has been implicated to have more systemic effects than other inhaled steroids, such as budesonide (BUD). The basis of this hypothesis is purely theoretical and is not supported by experimental data, however the lack of data has led to questions about the safety of inhaled FP being raised. This occurred most recently when the paediatric safety profile was the subject of several articles [Todd, 1996; Lipworth, 1999; Skoner, 2002]. The measurement of inhaled steroids in adipose tissue has not been investigated so far in man because there has been no validated method available for their measurement in adipose tissue. This study will help fill a gap in our knowledge regarding the tissue concentrations of inhaled corticosteroids. The reason that BUD has been chosen as the comparator steroid in this study, is because it has lower lipophilicity compared to FP and there is related to that a perception of an increase in safety due to less accumulation in adipose tissue compared to FP [Clark, 1997; Todd, 1996]. This two-part study will be performed in chronic asthmatic patients (Part A) and in healthy volunteers (Part B). The chronic asthmatic patients will be chosen on the basis that they are clinically stable and have been using either BUD or FP for at least three months prior to screening to allow steady state concentrations of BUD or FP to be measured. In the second part of the study, healthy subjects will be recruited to assess the time courses of drug levels in fat and to obtain data for PK modelling of adipose tissue concentrations. Objective(s) Primary 1. To compare the trough concentrations (normalised by dose) of FP and BUD in adipose tissue at steady state in asthmatic patients. Secondary Part A 1. To obtain the ratio of the trough concentration of FP in adipose tissue to trough concentration of FP in plasma at steady state in asthmatic patients. 2. To obtain the ratio of the trough concentration of BUD in adipose tissue to trough concentration of BUD in plasma at steady state in asthmatic patients. 9

24 3. To characterise the peak and trough concentrations of FP in plasma at steady state in asthmatic patients. 4. To characterise the peak and trough concentrations of BUD in plasma at steady state in asthmatic patients Part B 1. To characterise the time-course of adipose concentrations of FP in healthy subjects after multiple dosing. 2. To characterise the time-course of plasma concentrations of FP in healthy subjects after multiple dosing. 3. To characterise the time-course of adipose concentrations of BUD in healthy subjects after multiple dosing. 4. To characterise the time-course of plasma concentrations of BUD in healthy subjects after multiple dosing. Endpoint(s) Primary 1. Mean and 90% CI for trough concentrations (normalised by dose) of FP and BUD in adipose tissue at steady state in asthmatic patients. Secondary Part A 1. The ratio of the trough concentration of FP in adipose tissue to trough concentration of FP in plasma at steady state in asthmatic patients. 2. The ratio of the trough concentration of BUD in adipose tissue to trough concentration of BUD in plasma at steady state in asthmatic patients. 3. The trough and peak concentrations of FP in plasma at steady state in asthmatic patients. 4. The trough and peak concentrations of BUD in plasma at steady state in asthmatic patients. Part B 1. The trough concentrations of FP in adipose tissue before, during and after steady state in healthy subjects. 2. The trough concentrations of BUD in adipose tissue before, during and after steady state in healthy subjects. 3. The peak and trough concentrations of FP in plasma before, during and after steady state in healthy subjects. 10

25 4. The peak and trough concentrations of BUD in plasma before, during and after steady state in healthy subjects. 5. To determine the parameters relating to entry of drug from plasma to adipose tissues. These include plasma -fat tissue partition coefficient (Kp) and distribution rate constant (Kt) in adipose tissues for FP and BUD. Study Design 24 asthmatic patients will be recruited in terms of their asthma medication as follows: 12 patients who are already using BUD or Symbicort by inhalation at BUD doses of µg twice a day. At least 6 of these subjects will be on the high daily dose (800 µg). 12 patients who are already using FP (or SERETIDE * ) by inhalation at FP doses µg twice a day. At least 6 of these subjects will be on the high daily dose ( µg). These 24 patients will be recruited into 2 groups as follows: Group A-1 6 patients 3 patients on BUD alone or Symbicort (400 µg BID) 3 patients on FP alone or SERETIDE ( µg BID) Group A-2 Up to 18 patients These patients will only be recruited if the results from the assessment of drug concentrations from Group A-1 indicate that detectable concentrations will be achieved in Group A-2 and Part B. The 18 patients recruited into Group A-2 will only be recruited if the results from the assay to measure FP and BUD concentrations performed on the adipose and plasma samples collected from subjects in Group A-1 are satisfactory. All 24 patients will be required to participate in the following visits during Part A of the study regardless of whether they are recruited into Group A-1 or A-2: Screening Visit: Up to 6 weeks prior to Visit 1 * Symbicort is a Trade Mark of Astra Zeneca Registered in US Patent and Trademark Office SERETIDE is a Trade Mark of the GlaxoSmithKline group of companies 11

26 (establish clinical stability and suitability for adipose biopsy) Run-in period: For 2 weeks prior to Visit 1 Patients will be asked to keep a diary to record the administration of their medication over 2 weeks Visit 1: 1 day: biopsy at trough; plasma samples at peak and trough Follow-up Visit: 5-14 days after the biopsy taken at Visit 1 (to inspect biopsy site) Study Design for Part B Part B of the study will only take place if the assay results obtained from the first group of 6 asthmatic patients (Group A-2) are satisfactory. This will be an open-label, randomised, parallel group, repeat-dose study in 21 healthy subjects. Each subject will administer concomitant doses of FP (400 µg BID) and BUD (400 µg BID) inhaled via DISKUS and Turbuhaler respectively. Subjects will be randomised into one of two parallel groups: Group B-1 and Group B-2. These two groups will differ with regards to the length of time the subjects receive the investigational product (up to a maximum of 7 days) and when the two biopsies are performed during the study period. Group B-1 13 subjects Randomly assigned to 1-7 days dosing. 2 trough biopsies taken between Days 1-7 inclusive Peak and trough plasma samples taken Group B-2 8 subjects All subjects will receive 7 days dosing. 2 biopsies taken between Days 7-9 inclusive Serial plasma PK sampling on Day 7 Peak and trough plasma samples taken DISKUS is a Trade Mark of the GlaxoSmithKline group of companies Registered in US Patent and Trademark Office Turbuhaler is a Trade Mark of Astra Zeneca Registered in US Patent and Trademark Office 12

27 All 21 subjects will receive 2 biopsies during the treatment phase. Group B-1 The 13 subjects recruited into Group B-1, will be required to participate in the following study visits: Visits for Group B-1 Screening Visit: Up to 6 weeks prior to study start (to establish eligibility for adipose biopsy) Visit 1: First dose + plasma samples (peak and trough) (Day 1) Treatment period (1-7 days) Visit 2: (Days 1-7) Visit 3: (Days 1-7) First biopsy (trough) + plasma samples (peak and trough) Second biopsy (trough) + plasma samples (peak and trough) Subjects will administer a morning dose but no evening dose will be administered Follow-up visit: 5-14 days after Visit 3 (to inspect biopsy site) All biopsies will be taken at the trough time-point, which for this study will be within 1 hour prior to the morning dose on Visits 2 and 3. Blood samples will be taken from each subject to measure the levels of the investigational products in plasma as follows: Visit 1 One sample taken before start of dosing (trough) + 1 sample taken at 30 and 90 minutes post morning dose (peak) Visits 2 and 3 One sample taken before biopsy and morning dose (trough) + 1 sample taken at 30 and 90 minutes post morning dose (peak) 13

28 Group B-2 The 8 subjects recruited into Group B-2, will be required to participate in the following study visits: Visits for Group B-2 Screening Visit: Up to 6 weeks prior to study start (to establish eligibility for adipose biopsy) Visit 1: First dose + plasma samples (peak and trough) (Day 1) Treatment period (1-9 days) Visit 2: (Day 7) Visit 3: (Days 7-9) First biopsy (peak) + serial plasma samples for PK profile All subjects will administer a morning dose only Second biopsy* + plasma samples (peak (Day 7 only) and trough) *Peak biopsies taken if Visit 3 occurs on Day 7 Trough biopsies taken if Visit 3 occurs on Day 8 or 9 Follow-up visit: 5-14 days after Visit 3 (to inspect biopsy site) The two biopsies will be performed between Days 7-9 inclusive according to the randomisation schedule. Biopsies performed on Day 7 will be performed at post morning dose (see Section 8.2 for details of when these samples will be taken). Biopsies performed on Days 8 and 9 will be performed as trough samples i.e. taken within 1-hour prior to the theoretical morning dosing time point as subjects will not receive doses on Days 8 and 9. All subjects will have blood samples taken to measure the levels of investigational products in plasma as follows: Visit 1 One sample taken before dosing (trough) + 1 sample taken at 30 and 90 minutes post morning dose (peak) Visit 2 Blood samples will be taken at various time-points during Day 7 to obtain a plasma PK profile (please refer to Appendix 1, Time and Events Table) 14

29 Visit 3 If Visit 3 is on Day 7, then serial plasma sampling will be performed as described for Visit 2. If Visit 3 is on Days 8 or 9, then 1 sample will be taken at the theoretical trough time point. Study Population A total of 24 asthmatic patients will be recruited into Part A of the study. A total of 21 healthy subjects will be recruited into Part B of the study. Inclusion Criteria A subject will be eligible for inclusion in this study only if all of the following criteria apply: Asthmatic Patients 1. Male or female, aged 18 to 60 years inclusive. Women will be eligible to enter the study if they are: Not pregnant or nursing Non child-bearing potential is defined as pre-menopausal females with documented (medical report verification) hysterectomy or surgical sterilisation, or post-menopausal women who have been amenorrheic for more than 1 year and have estradiol and FSH levels consistent with menopause. At least, a one week interval between screening and first study drug administration will be observed Of child-bearing potential and using an appropriate method of contraception with a documented failure rate of less than 1% per year for the duration of the study and for 1 month after the last administration of investigational products. Contraception considered appropriate for this study is: complete abstinence from intercourse for 2 weeks before exposure to the study drug, throughout the clinical trial, and until the follow-up procedures have been completed; female sterilisation; oral contraception drugs (in combination with a second method of contraception e.g. condoms), implants or injectable; any intrauterine device (IUD); a barrier method of contraception must only be used in combination with another method of contraception as listed above. 2. Non smoker within 6 months of the start of the study, and with a total pack year history of 10 pack years. 3. Considered suitable for anterior abdominal wall adipose tissue biopsy in the opinion of the investigator. 4. Clinically stable patients (FEV 1 % predicted) with medically diagnosed asthma which is currently being treated with inhaled FP ( µg daily, alone or as SERETIDE) or BUD ( µg daily, alone or as Symbicort) and has been treated using with the same dosage for at least three months prior to screening. 15

30 5. No clinical laboratory abnormality at screening. Subjects with laboratory parameters outside the reference range for this age group will only be included if the investigator considers that such findings will not introduce additional risk factors. 6. Able and willing to give written informed consent to take part in the study. 7. Available to complete all study measurements. 8. A negative Hepatitis B and C surface antigen at screening. 9. A normal 12-lead ECG at screening. 10. Not taking FP or BUD by any route other than inhaled (e.g. skin, intranasal). 11. No exposure to CYP3A4 inhibitors within 1 month before screening or during the study. Healthy Subjects 1. Male or female, aged 18 to 60 years inclusive. Women will be eligible to enter the study if they are: 2. Not pregnant or nursing 3. Of child-bearing potential and using an appropriate method of contraception with a documented failure rate of less than 1% per year for the duration of the study and for 1 month after the last administration of investigational products. Contraception considered appropriate for this study is: complete abstinence from intercourse for 2 weeks before exposure to the study drug, throughout the clinical trial, and until the follow-up procedures have been completed; female sterilisation; oral contraception drugs (in combination with a second method of contraception e.g. condoms), implants or injectable; any intrauterine device (IUD); a barrier method of contraception must only be used in combination with another method of contraception as listed above. 4. Non child-bearing potential is defined as pre-menopausal females with documented (medical report verification) hysterectomy or surgical sterilisation, or postmenopausal women who have been amenorrheic for more than 1 year and have estradiol and FSH levels consistent with menopause. At least, a one week interval between screening and first study drug administration will be observed. 5. Non smoker within 6 months of the start of the study, and with a total pack year history of 10 pack years. 6. Considered suitable for anterior abdominal wall adipose tissue biopsy in the opinion of the investigator. 7. No abnormality on clinical examination. A subject with a clinical abnormality may be included only if the investigator considers that the abnormality will not introduce additional risk factors and will not interfere with the study procedure. 8. No abnormality on clinical chemistry or haematology examination at screening. Subjects with laboratory parameters outside the reference range for this age group will only be included if the investigator considers that such findings will not introduce additional risk factors. 16

31 9. A normal 12-lead ECG tracing at the screening visit. 10. A negative urine screen for drugs of abuse at screening. 11. A negative Hepatitis B and C surface antigen result at screening. 12. Not taking FP or BUD by any route other than inhaled (e.g. skin, intranasal). 13. No exposure to CYP3A4 inhibitors within 1 month before screening or during the study. Exclusion Criteria A subject will not be eligible for inclusion in this study if any of the following criteria apply: Asthmatic Patients 1. Has had a clinical exacerbation of asthma within 3 months of screening. 2. Received treatment with oral corticosteroids within 2 months of the screening visit. 3. Has history of abnormal bruising or bleeding. 4. Has an abnormal blood coagulation profile (as shown by measuring PT and PTT). 5. Is unable to lie flat for biopsy. 6. History of blood donation such that a subject will have donated more than 1500 ml blood for males and 1000 ml for females within the last 12 months if they participate in this study. Female subjects may give no more than 500 ml blood over a 6 week period and males no more than 750 ml over a 6 week period. 7. Participation in a trial with a new chemical entity within 112 days before the screening visit or any marketed product within 84 days of the screening visit. 8. History of neurological or psychiatric disease which would interfere with the subject s proper completion of the protocol assignment. 9. History of drug or alcohol abuse (defined as an average daily intake of more than 3 units for males and more than 2 units for females One unit of alcohol is defined as a medium (125 ml) glass of wine, half a pint (250 ml) of beer or one measure (24 ml) of spirits) which would interfere with the subject s proper completion of the protocol assignment. Healthy Subjects 1. Received treatment with oral corticosteroids within 2 months of the screening visit. 2. History of abnormal bruising or bleeding. 3. Has an abnormal blood coagulation profile (as shown by measuring PT and PTT) 4. Is unable to lie flat for biopsy. 5. History of blood donation such that a subject will have donated more than 1500 ml blood for males and 1000 ml for females within the last 12 months if they 17

32 participate in this study. Female subjects may give no more than 500 ml blood over a 6 week period and males no more than 750 ml over a 6 week period. 6. Participation in a trial with a new chemical entity within 112 days before the screening visit or any marketed product within 84 days of the screening visit. 7. History of neurological or psychiatric disease which would interfere with the subject s proper completion of the protocol assignment. 8. History of drug or alcohol abuse (defined as an average daily intake of more than 3 units for males and more than 2 units for females One unit of alcohol is defined as a medium (125 ml) glass of wine, half a pint (250 ml) of beer or one measure (24 ml) of spirits) which would interfere with the subject s proper completion of the protocol assignment. 9. Known or suspected history of adverse reactions or hypersensitivity to corticosteroids (including FP and BUD). 10. Use of prescription or non-prescription drugs other than paracetamol (up to 4 g per day for the treatment of minor ailments eg headache), herbal supplements or vitamins other than within recommended dosages within 7 days prior to Visit 1 and throughout the course of the study. 11. Unable to use DISKUS or Turbuhaler after training Study Assessments and Procedures In addition to demographic data, the following assessments will be conducted at screening: Asthmatic Patients Healthy Subjects Complete medical history, including smoking status and tobacco and alcohol use history Complete medical history, including smoking status and tobacco and alcohol use history Medication history Medication history Physical examination including vital signs Physical examination including vital signs Standard 12-lead ECG Standard 12-lead ECG Blood and urine samples for safety assessment (haematology, clinical chemistry, urinalysis, coagulation parameters (PT and PTT), serology) FEV 1 and FVC measurements highest of 3 efforts Blood and urine samples for safety labs (haematology, clinical chemistry, urinalysis, coagulation parameters (PT and PTT), serology) FEV 1 and FVC measurements - highest of 3 efforts Inhaler training Inhaler training Pregnancy test for females of CBP Pregnancy test for females of CBP 18

33 Patients who successfully pass the screening visit, will be required to participate in a runin period for 2 weeks prior to Visit 1. Patients will be required to have a FEV 1 assessment (best of 3 efforts) at the start of the run-in period. The following assessments will be done at various time points during the study (please refer to the Time and Events Tables in Appendix 1): 12-lead ECG; vital signs; safety labs; coagulation parameters; serology; drugs of abuse; PK and PGx samples; FEV1/FVC; pregnancy testing; AE/SAE assessment Investigational Product(s) Part A During Part A of the study, the asthmatic patients will continue using their own supply of FP (or SERETIDE) at doses of µg twice daily or BUD (or Symbicort) at doses of µg twice daily, according to their usual routine. Part B For Part B of the study: Fluticasone propionate (100 µg per actuation) will be supplied as FLIXOTIDE and will be supplied pre-packed into DISKUS inhalers by the study site. Budesonide (400 µg per actuation) will be supplied as Pulmicort and will be supplied pre-packed into Turbuhaler inhalers by the study site. The healthy subjects will inhale FP via the DISKUS inhaler. The FP will be administered at 100 µg per actuation. Therefore subjects will be required to administer 4 actuations of FP (400 µg) in the morning and administer another 4 actuations (400 µg) in the evening to receive a total dose of 800 µg per day. The subjects will inhale BUD via the Turbuhaler inhaler. The BUD will be administered at 400 µg per actuation. Therefore subjects will be required to administer 1 actuation of BUD (400 µg) in the morning and administer another 1 actuation (400 µg) in the evening to receive a total dose of 800 µg per day FLIXOTIDE is a Trade Mark of the GlaxoSmithKline group of companies Registered in US Patent and Trademark Office Pulmicort is a Trade Mark of Astra Zeneca Registered in US Patent and Trademark Office 19

34 1. INTRODUCTION 1.1. Background It has been suggested that fluticasone propionate (FP), being highly lipophilic, partitions into tissues and therefore, despite its low plasma levels, may result in tissue accumulation and a higher total systemic load than less lipophilic inhaled steroids [Clark, 1997; Källén, 2003]. Thus, FP has been implicated to have more systemic effects than other inhaled steroids, such as budesonide (BUD). The basis of this hypothesis is purely theoretical and is not supported by experimental data. However, the lack of data has led to questions about the safety of inhaled FP being raised. This occurred most recently when the paediatric safety profile was the subject of several articles [Todd, 1996; Lipworth, 1999; Skoner, 2002]. The measurement of inhaled steroids in adipose tissue has not been investigated so far in man because there has been no validated method available for their measurement in adipose tissue Pharmacogenetics Pharmacogenetics (PGx) is the study of variability in drug handling or response due to hereditary factors in different populations. There is increasing evidence that an individual's genetic composition (i.e., his or her genotype) may impact the pharmacokinetics (absorption, distribution, metabolism, elimination), pharmacodynamics (relationship between concentrations and pharmacologic effects or the time course of pharmacologic effects) and/or the incidence of adverse events for a given investigational product. Some reported examples of PGx analysis are shown in Section 1.2, Table 1: Table 1 Reported Examples of PGx analysis Drug Disease Gene Outcome Clozapine Schizophrenia [Arranz, 1995] 5HT2A Patients homozygous for the C102 allele appear more frequently in the nonresponder (53%) than in the responder group (26%) Pravastatin Coronary Atherosclerosis [Kuivenhoven, 1998] Cholesteryl ester transfer protein (CETP) Progression of coronary atherosclerosis slowed in B1/B1 homozygotes but not in B2/B2 homozygotes receiving pravastatin Desipramine Depression [Daly, 1995] CYP2D6 Poor metabolizing genotypes at risk of drug accumulation and associated toxicity 20

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