A Single Centre Study in Healthy Volunteers to Optimise the Rotacap Formulation and ROTAHALER Device for Delivery of Fluticasone Propionate/Salmeterol
Condition: Asthma
MeSH terms: Asthma
Study type: Interventional
Phase: Phase 1

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.
    

Detailed description: 
      BACKGROUND:

      Asthma is a chronic inflammatory disease of the airways characterised by varying and
      recurring symptoms of shortness of breath, chest tightness, wheezing and cough, airflow
      obstruction, bronchial hyper-responsiveness and underlying inflammation.

      The GINA guidelines [Global Initiative for Asthma,(GINA) updated 2009] highlight the need to
      treat airway inflammation in asthma and recognise the importance of inhaled prophylactic
      medications such as inhaled corticosteroids and combinations of Inhaled Corticosteroids (ICS)
      / Long Acting Beta Agonists (LABA) such as SERETIDE™ for the treatment of chronic asthma.

      Chronic obstructive pulmonary disease (COPD) is a preventable and treatable disease
      characterised by airflow limitation that is not fully reversible [Celli, 2004]. The airflow
      limitation of COPD is primarily due to small airways disease and parenchymal destruction
      associated with an abnormal inflammatory response of the lungs, mainly caused by cigarette
      smoking [Celli 2004]. COPD is characterised by symptoms of chronic and progressive
      breathlessness (or dyspnea), cough and sputum production which can be a major cause of
      disability and anxiety associated with the disease.

      The GOLD (Global Strategy for the Diagnosis, Management and Prevention of Chronic Obstructive
      Pulmonary Disease) guidelines on COPD state that the goals of pharmacologic therapy should be
      to control symptoms, improve health status and exercise tolerance, and reduce the frequency
      of COPD exacerbations [GOLD, 2008]. Research has indicated that an inhaled corticosteroid
      (ICS) combined with a long acting β2-agonist (LABA) is more effective than the individual
      components in managing stable COPD to reduce exacerbations and improve lung function and
      health status [Ferguson, 2008; Calverley, 2007; Kardos, 2007].

      The efficacy of the combination product, SERETIDE has been established in the metered dose
      inhaler (MDI) and multidose powder inhaler (Ddpi; DISKUS™/Accuhaler) in both asthma and
      Chronic Obstructive Pulmonary Disease, COPD at a variety of dose strengths.

      Alternative treatment options with respect to the formulation of SERETIDE and its means of
      delivery via an inhaler device are currently being assessed by GSK with a view to developing
      a product with bioavailability characteristics comparable to those of SERETIDE delivered via
      the multi-dose powder inhaler (DISKUS™/Accuhaler). It is intended that the product will then
      be progressed for treatment administration in both asthma and COPD patients.

      STUDY RATIONALE:

      A recently completed study, ASR114334, [GlaxoSmithKline document number YM2010/00082/02]
      evaluated the comparative bioavailability of fluticasone propionate/salmeterol delivered via
      the established multi-dose powder inhaler (Ddpi, DISKUS/Accuhaler) with the Rotahaler unit
      dose fluticasone propionate/salmeterol capsule-based powder inhaler (Rdpi) in both asthma and
      COPD patients. The Rotahaler (Rdpi) inhaler had an airflow resistance similar to the DISKUS
      multi-dose inhaler (Ddpi). Whilst the active ingredients were a combination of fluticasone
      propionate/salmeterol, the devices were different with respect to their handling and
      instructions for operation, although both were designed to deliver at the 250/50mcg bid dose
      strength ie mcg equivalent doses.

      The results showed that plasma exposures of both fluticasone propionate (FP) and salmeterol
      were 1.5 to 2 fold higher following repeat dose administration of FP/salmeterol delivered
      from the Rdpi compared with those from the Ddpi, [GlaxoSmithKline document number
      2011N112456_00]. This was observed for both asthma and COPD patients.

      The purpose of this study, ASR116409 is to optimise the device and/or formulation of the
      FP/salmeterol unit dose powder inhaler to achieve drug delivery characteristics comparable to
      the FP/salmeterol DISKUS.

      DOSE RATIONALE:

      Two doses of FP/salmeterol will be administered in this study: 250/50 mcg and 100/50 mcg or
      lower, both doses are approved for the treatment of asthma. These doses will be administered
      to healthy subjects and are at or below the maximum approved doses for FP and salmeterol
      indicated for chronic therapy in asthma; therefore there are no anticipated safety concerns
      associated with the planned short term (3.5 days bid) dosing in healthy subjects.

      STUDY DESIGN:

      The study is an open-label, randomised, cross-over, single centre study in healthy volunteers
      in 3 parts, A, B and C. It will be conducted with an adaptive design where pharmacokinetic
      data analysis follows each part to enable a decision on whether progression to the subsequent
      parts is required.

      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. Subjects may elect to participate in more than one part.

      Part A will compare the bioavailability characteristics of the following GSK devices: the
      Ddpi (multi-dose dry powder inhaler, DISKUS), the Rdpi(H) (capsule-based inhaler, high
      airflow resistance) and the Rdpi(L) (low airflow resistance). The Rdpi(H) has higher airflow
      resistance to the Ddpi compared to the Rdpi (L) and could allow a closer PK match. Part A
      will consist of a four treatment cross-over sub-study with the following arms, each arm
      replicated twice for each subject.

      Treatment arms for part A will comprise:

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Ddpi

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Rdpi(H). Instructions for subjects will be to take 2 steady, deep inhalations.

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Rdpi(L). Instructions for subjects will be to take 1 fast and deep inhalation

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Rdpi(L). Instructions for subjects will be to take fast and deep inhalations until no
           powder remains in the inhaler.

      The Rdpi(H) device (250/50mcg FP/salmeterol) is being assessed in Part A to bridge the data
      back to the previous study (ASR114334) to show whether it is possible to replicate the 1.5 to
      2 fold systemic exposure ratio for Rdpi(H)/Ddpi in healthy subjects compared to patients seen
      in the previous study (ASR114334).

      Subjects will be dosed twice daily for 3 days and once on the fourth day in the morning. The
      first dose on Day 1 will be administered at the site and the next four doses will be
      self-administered by the subjects at home. They will attend the Unit in the evening of the
      3rd day where they will be administered the 6th dose and remain at the Unit for the night and
      following day. They will be dosed in clinic (7th dose) on the morning of the fourth day and
      remain at site until completion of the 12 hour post-dose PK sample collection.

      Following a 3-day minimum wash-out period after the last dose of study medication (Day 4),
      subjects will participate in the subsequent arms of Part A until they have completed all 4
      arms twice i.e. the 8 periods planned for completion of Part A.

      PK samples will be analysed and reviewed at the conclusion of Part A. If PK equivalence for
      FP and SALM is demonstrated between the Rdpi(L)and the Ddpi, and Rdpi(H)is demonstrated to
      have higher and non-equivalent PK systemic exposure compared to Ddpi, Part C will be
      conducted. If PK equivalence is not demonstrated, Part B will be conducted.

      Part B: Study design for Part B will depend on the PK results from Part A. Prior to the start
      of part B, a decision will be made by the sponsor team as to whether the Rdpi (H) or the
      Rdpi(L) device will be used; this decision will be based on PK data from part A. FP/Salm
      250/50mcg from the Ddpi will be included again in Part B as a control group.

      If the plasma exposures of FP and SALM obtained during Part A from Rdpi(H) are statistically
      higher than those from the Dpi and those from Rdpi (L) are statistically lower than those
      from the Ddpi, Part B will assess two intermediate airflow resistance versions of the Rdpi
      [Rdpi (IM)] and/or the formulation changes below:

        -  modified blend formulations

        -  reduced capsule fill weights,

        -  different capsule types If the plasma exposures of FP and SALM obtained from the Rdpi(H)
           are statistically higher than those from the Dpi and those from the Rdpi(L) are
           statistically higher than those from the Ddpi, Part B will assess the formulation
           changes below using Rdpi(H);

        -  modified blend formulations

        -  reduced capsule fill weights,

        -  different capsule types One variable will be assessed at a time in an open-label,
           randomized, cross-over manner comprising 2 to 3 arms separated by a 3-day minimum
           wash-out period. All comparisons will be done against the DISKUS arm, in order to test
           bioequivalence. The sample size and the use of replicated arms will be evaluated and
           defined after the completion of part A, adapting the design and the sample size to the
           variability observed during the previous part of the study.

      Following PK data analysis for all the variables, two or more variables may finally be
      grouped for combined assessment as an open-label investigation.

      Evaluation of the two intermediate high airflow resistance Rdpi devices [Rdpi(IM)] and of the
      formulation changes will be conducted in a cross-over design. The inhalation instructions
      (number and type of breaths) will be decided after Part A is completed. An additional arm
      whereby subjects will be administered the Ddpi will also be included for comparison.

      Part C will compare bioavailability parameters for 2 dosage strengths of FP/salmeterol:
      100/50 mcg, and 250/50mcg, delivered from the Ddpi and the device/formulation shown to
      demonstrate bioequivalence in Part A and/or Part B.

      Another GSK unit dose device in development, the BUDI inhaler, will also be evaluated for its
      comparative bioavailability characteristics at both doses.

      If PK data from Part A demonstrates that the Rdpi(L) is PK equivalent to the Ddpi at the
      250/50 mcg dose, Part B will not be conducted. We will also test the bovine capsule which may
      be needed for certain markets in Part C if Part B is not conducted.

      The various arms in Part C will not be conducted concurrently as timing of dosing for each
      arm will depend on availability of study medication, device and capsule type.

      Part C will therefore be conducted at two different points in time: Part C1 will consist of a
      3 or 4-way cross-over sub-study with the following arms:

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Ddpi

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
           Ddpi

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
           device/formulation combination selected in Part A or B

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Bovine capsule (if part B is not performed).

      Part C2 will be performed if required when the BUDI inhaler will be made available, a
      cross-over sub-study with the following arms:

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via the
           Ddpi

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
           Ddpi

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (250/50mcg) delivered via BUDI
           Inhaler

        -  Administration of 7 doses (3.5 days bid) of FP/salmeterol (100/50mcg) delivered via the
           BUDI Inhaler.

      The inhalation instructions (number and type of breaths) will be decided after part A is
      completed

      The option to combine Parts C1 and C2 will be evaluated according to the:

        -  availability of the BUDI Inhaler and the timing of Part C

        -  PK results from the previous parts (variability could affect the need to have replicated
           arms in part C as well; further, the bovine capsule may have been already tested in part
           B).

      PRIMARY OBJECTIVES:

        -  To select 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 (multi dose dry
           powder inhaler)

        -  To compare the 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 in healthy
           volunteers.

      SECONDARY OBJECTIVES:

        -  To determine 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 the 100/50mcg dose from the Ddpi

        -  To assess the PK characteristics of the BUDI inhaler containing 100/50mcg fluticasone
           propionate/salmeterol and 250/50mcg fluticasone propionate/salmeterol.

      PRIMARY ENDPOINT:

      -Pharmacokinetic endpoint: Area under the plasma fluticasone propionate concentration-time
      curve over dosing interval ; maximum observed concentration for fluticasone propionate and
      salmeterol plasma concentration-time curve on the last day of each study treatment period
      (Day 4).

      SECONDARY ENDPOINT:

      -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).

      TREATMENT ASSIGNMENT:

      During Part A of the study, subjects will be assigned to one of the four sequences of the
      below reported table (4x4 Williams design with replicates) in accordance with the
      randomization schedule generated by Quantitative Sciences, prior to the start of the study,
      using validated internal software.

      Sequence number Arm

        1. A B D C D A C B

        2. B C A D C D B A

        3. C D B A B C A D

        4. D A C B A B D C

      A indicates Ddpi, B indicates Rdpi(H), C indicates Rdpi(L) fast and deep inhalation, and D
      indicates Rdpi(L) fast and deep inhalations until no powder remains in the inhaler.

      Williams design, with replicates or not, will be adopted for the subsequent and optional
      parts of the study, depending on the results obtained in part A.
    

Intervention name(s): SERETIDE Rotacaps; SERETIDE Diskus
Intervention type(s): Drug; Drug
Intervention description(s): 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.; 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 MeSH terms: Fluticasone-Salmeterol Drug Combination
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Asthma; Respiratory; COPD