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

NCT01540708 | Completed Phase 1

• 1 other identifier: 116409
• Study Type: interventional
• Target: 36
• Locations: 1 country
• Sites: 1

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.

Conditions

Asthma

Keywords

Asthma; Respiratory; COPD

Outcome Measures

Primary Outcomes (2)

• 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

  PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose

• 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).

  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 Outcomes (2)

• 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

  PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose

• Assessment of the PK characteristics of the BUDI inhaler containing 100/50mcg fluticasone propionate/salmeterol and 250/50mcg fluticasone propionate/salmeterol

  PK on Day 4 of each treatment arm: 0, 5, 10, 30 min and 1, 2, 4, 8, 10 and 12 hours post-dose

Study Arms (2)

SERETIDE Rotacaps

EXPERIMENTAL

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

SERETIDE Diskus

ACTIVE COMPARATOR

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

Interventions

SERETIDE Rotacaps DRUG

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.

SERETIDE Diskus

SERETIDE Diskus DRUG

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.

SERETIDE Rotacaps

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

• 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.
• 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.
• 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.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (1)

GSK Investigational Site

Randwick, New South Wales, 2031, Australia

Location

Related Publications (11)

• 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. doi: 10.1056/NEJMoa063070.

  PMID: 17314337 BACKGROUND

• 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. doi: 10.1183/09031936.04.00014304. No abstract available.

  PMID: 15219010 BACKGROUND

• 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.

  PMID: 18614347 BACKGROUND

• GINA: Global strategy for asthma management and prevention. NHLBI/WHO/GARD, Washingon DC 2006-updated 2009.

  BACKGROUND

• GlaxoSmithKline Document Number RM2007/00413/03. CCI18781+GR33343 Investigator's Brochure, version number 12, dated 4 May 2011.

  BACKGROUND

• 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.

  BACKGROUND

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

  BACKGROUND

• 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.

  PMID: 19439490 BACKGROUND

• 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. doi: 10.1164/rccm.200602-244OC. Epub 2006 Oct 19.

  PMID: 17053207 BACKGROUND

• 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. doi: 10.1007/BF01068419.

  PMID: 3450848 BACKGROUND

• GlaxoSmithKline document number 2011N112456_00 Study report for 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.

  RESULT

Related Links

• Results for study 116409 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Asthma; Pulmonary Disease, Chronic Obstructive

Condition Hierarchy (Ancestors)

Bronchial Diseases; Respiratory Tract Diseases; Lung Diseases, Obstructive; Lung Diseases; Respiratory Hypersensitivity; Hypersensitivity, Immediate; Hypersensitivity; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 23, 2012
• First Posted: February 29, 2012
• Study Start: January 16, 2012
• Primary Completion: September 4, 2012
• Study Completion: September 4, 2012
• Last Updated: June 19, 2018

Record last verified: 2018-06

Locations

AU (1)