Urine Concentrations of Vilanterol After Inhaled Administration of Vilanterol/Fluticasone Furoate
Condition: Pharmacokinetics
Study type: Interventional
Phase: Phase 2

Summary: 
      Introduction: The prevalence of asthma and exercise-induced bronchoconstriction is high in
      the athletic population. In endurance sport, the prevalence has been reported to be as high
      as 30-50% compared to the general population prevalence of approximately 5-10% in Western
      countries. First-line treatment in asthma is reliever medication and inhaled corticosteroids
      (ICS). Therefore, β2-adrenoceptor agonists and ICS are commonly prescribed drugs to athletes.
      Although long-acting β2-agonists (LABA) are the most commonly used β2-agonists in asthma
      management, development of ultra-long acting β2-agonists (U-LABA) as vilanterol may change
      this. U-LABA has a long duration of action (24 hours) compared with LABA (12 hours). The
      accumulated number of inhalations per day for elite athletes may thus be reduced when
      prescribed with U-LABA as compared to LABA. Use of β2-agonists are restricted by the World
      Anti-Doping Agency (WADA). As of 2018, β2-agonists salbutamol, formoterol and salmeterol are
      allowed by inhalation in therapeutic doses, whereas other β2-agonists, such as terbutaline
      and vilanterol still require the athlete to obtain a therapeutic use exemption (TUE). To
      discriminate therapeutic use from supra-therapeutic misuse, WADA has established urinary
      thresholds and decision limits based on urine concentrations of salbutamol, salmeterol and
      formoterol. However, while data on urine concentrations of these three β2-agonists are
      well-described in studies that simulate sport-specific situations that are applicable for
      doping control, no such data exist for the novel U-LABA vilanterol. For instance, asthmatic
      athletes using β2-agonists usually inhale the drug before training or competition as
      prophylaxis for bronchoconstriction. Thus, studies are needed to investigate the urine
      concentrations of vilanterol after inhaled administration in set-ups that are applicable to
      doping control which this study aims to investigate.

      Method: The study is divided in two phases. The first phase consists of a pharmacokinetic
      pilot trial (EXP1). Depending on the analytical outcome of the pilot study, the study
      proceeds into the second phase, which is a larger pharmacokinetic trial (EXP2). Both EXP1 and
      EXP 2 are open label studies.

      EXP1: 6 healthy, well trained individuals are recruited to perform two trial days. First
      trial day consists of inhalation of the study drug in 4 times therapeutic dose followed by an
      exercise session. Before second trial day subjects inhales 4 times the therapeutic dose at
      home and on day 7 perform a training session. Urine and blood are collected in the following
      72 hours both days.

      EXP2: 20 healthy, well trained individuals are recruited to perform four trial days in the
      same way as EXP1. But here both normal use and four times normal dose is investigated.
    

Detailed description: 
      OBJECTIVES The main objective of the present study is to investigate urine concentrations of
      vilanterol and its metabolites (GSK932009 and GW630200) after single dose inhalation of
      Relvar® (22/184 mcg VI/FF) at therapeutic and supratherapeutic doses. A secondary objective
      is to investigate whether vilanterol and its metabolites (GSK932009 and GW630200) are present
      at higher concentrations in urine after seven days of daily inhalation of Relvar® at
      therapeutic and supratherapeutic doses.

      Applicability The results from the study will help establish a urine threshold and decision
      limit for vilanterol on the WADA list of prohibited substances, thus lessening the
      administrative burdens associated with TUEs.

      Study drug Study treatment in this study is refers to either therapeutic dosage of 22/184
      micrograms of vilanterol/fluticasone furoate or four times therapeutic dosage of
      vilanterol/fluticasone furoate (88/736 micrograms, 4 puffs).

      METHODS Study design The study is divided in two phases. The first phase consists of a
      pharmacokinetic pilot trial (EXP1). Depending on the analytical outcome of the pilot study,
      the study proceeds into the second phase which is a larger pharmacokinetic trial (EXP2).

      Progression from the pilot phase (EXP1) of the study to the second phase (EXP2) of the study
      depends on a successful pilot phase (EXP1). Success will be concluded provided the pilot
      phase generates adequate urine concentration data for vilanterol and/or its metabolites
      (GSK932009, GW630200) with values above the assay limits of quantitation for at least 8 hours
      post dose. The pilot phase urine concentration data, together with plasma concentration data,
      will also be used to estimate the urinary concentrations of vilanterol and/or its metabolites
      at therapeutic and supratherapeutic under various conditions. These estimates will be used to
      determine whether progression to the second phase of the study is feasible and has a high
      probability of success in achieving its objectives.

      Type of study The study is an open-label study. The study is classified as a Phase II study
      investigating pharmacokinetics Screening In EXP1 and EXP2, subjects are examined by a medical
      doctor and electrocardiography (ECG) is performed. Furthermore, subjects' lung function is
      measured with a spirometer and maximal oxygen consumption (VO2max) and performance are
      determined during an incremental bike ergometer test to exhaustion. Prior to the test,
      subjects warm up for 15 min. Subjects are told to keep a cadence of 80-100 rpm during the
      test. During the warm-up and incremental test, gas exchange is measured breath-by-breath.

      After the VO2max-test, inhaler technique is practiced with a demonstrator device.

      Pharmacokinetic trials

      In EXP1, subjects meet at the laboratory for two trials:

      Trial A1: Supra-therapeutic inhalation of Relvar® 22/184 (4 puffs) once Trial A2:
      Supra-therapeutic inhalation of Relvar® 22/184 (4 puffs) daily for 7 days

      In EXP2, subjects meet at the laboratory for four trials:

      Trial A1: Supra-therapeutic inhalation of Relvar® 22/184 (4 puffs) once Trial A2:
      Supra-therapeutic inhalation of Relvar® 22/184 (4 puffs) daily for 7 days Trial B1:
      Therapeutic inhalation of Relvar® 22/184 (1 puff) once Trial B2: Therapeutic inhalation of
      Relvar® 22/184 (1 puff) daily for 7 days

      During each of the trials, subjects meet in the morning after an overnight fast. A urine
      sample is collected and subjects ingest a standardized meal and drink. One hour after the
      meal, study drug is administered during supervision and subjects start performing 60 min of
      exercise on a bike ergometer. Exercise is based on subjects' individual VO2max. To simulate
      the shifts in intensity during real-life competitive stages, the exercise protocol is
      performed at various shifting intensities, but still at a relative load of subjects' VO2max
      for inter-individual comparisons. Subjects are allowed to drink water during the exercise.

      After exercise, subjects remain inactive for the rest of the trial. Three hours after
      administration of the study drug, subjects receive a standardized lunch and drink.

      Urine is collected 0-1, 1-2, 2-4, 4-6, 6-8, 8-12, 12-16, 16-24, 24-36, 36-48 and 48-72 h
      following administration (corresponding to 0-71 h post exercise).

      Venous blood samples are collected through a catheter in the antecubital vein ½, 1½, 3, 5, 7
      and 10 h following administration.

      Detailed instructions for urine and blood sample collection, processing, storage and
      transportation will be provided in the Study Procedures Manual) Concerning the Pilot study
      (EXP1) and the main study (EXP2): Between trials 1 and 2, subjects receive a Relvar® inhaler
      for six days of home use of 4 puffs per day, which will be monitored by staff via Skype or
      Facetime video call at the same time of the day as during trial 1. Twenty-four hours after
      the sixth day of home inhalation, subjects meet for trial 2. In EXP1 Trial A1 and Trial A2 is
      separated with minimum one week to ensure washout. In EXP2, Trial A1 and A2 and B1 and B2 are
      separated by at least 1 week to ensure washout.

      End of trial The trial is finished when the last patient has been at the last visit. Pilot
      study (EXP1) is estimated to end at the end of 2018 and the large study is estimated to end
      at the end of 2019.
    

Intervention name(s): Fluticasone Furoate/ Vilanterol Trifenatate
Intervention type(s): Drug
Intervention description(s): Asthma inhalation medication
Other intervention name(s): Relvar Ellipta 184/22 micrograms
Intervention MeSH terms: Fluticasone; Xhance
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Basic Science