Atrovent in Exercise Induced Laryngeal Obstruction (EILO)
Condition: Exercise Induced Laryngeal Obstruction (EILO)
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Exercise Induced Laryngeal Obstruction (EILO) is a condition not uncommon in otherwise
      healthy young people. EILO is caused by posteromedial collapse of supraglottic structures or
      medialization of the vocal folds, or both, during high intensity exercise. There are
      currently no treatments available that is properly evidence based. However, case reports
      suggest a possible effect from the "asthma drug" Ipratropium Bromide (Atrovent®). The current
      project is an open label pilot study, aiming to test if Atrovent can influence the occurence
      of EILO, either postponing the onset during exercise or fully prevent the condition to occur.
    

Detailed description: 
      Exercise induced inspiratory symptoms (EIIS) is increasingly recognized as an important
      differential diagnosis to exercise induced asthma (EIA) in otherwise healthy adolescents.
      EIIS is most often linked to laryngeal abnormalities and if so, often labelled exercise
      induced laryngeal obstruction (E-ILO). In unselected populations, E-ILO has been found in
      7.5% and 5.7% of adolescents. Causal mechanisms remain unclear, and a variety of structural
      and/or functional pathways have been proposed, such as abnormalities related to the
      epiglottis, the laryngeal cartilage-skeleton or its support, mucosal structures as well as
      the laryngeal muscular system or its nerve supply. All these abnormalities might conceivably
      disturb the airflow on its way through the laryngeal inlet, increase the turbulence and the
      airflow resistance, and thereby set up a sense of dyspnea and trigger the symptoms that are
      characteristic of EIIS. Additionally, various psychological characteristics have been
      proposed to be implicated in this causal cascade.

      As the causal mechanisms of E-ILO have not been clarified, all attempts on treatment of this
      condition have been empirical and there is currently no properly evidence-based treatment
      available. Speech therapy, often in combination with some kind of psychotherapy, have been
      viewed as mainstay therapy by most authors, whereas other psychological measures such as
      relaxation therapy, hypnosis and biofeedback have been advocated by others. Anticholinergic
      aerosols applied before exercise has been suggested and there are reports of successful
      surgical treatment using laser supraglottoplasty. The common goal of these treatment
      initiatives has been to increase the size of the laryngeal inlet during the increasing
      airflow velocity that is induced by increasing exercise intensity.

      Inducible laryngeal obstructions were previously often labeled vocal cord dysfunction (VCD),
      and Ayres et al. proposed in 2002 in an article in Thorax that VCD could be a function of an
      altered autonomic balance. This view opened for a theoretical framework for treatment of VCD
      using inhaled anticholinergic agents such as Ipratropium bromide (Atrovent®).

      To our knowledge, positive effects from inhaled anticholinergic agents in VCD have so far
      only been published as case reports, and systematic studies have not been performed.

      This study aims to address potential effects from Atrovent in patients with E-ILO verified
      during a continuous laryngoscopy exercise (CLE) test. The study will primarily include 20
      patients consecutively referred to our clinic for EIIS and diagnosed with E-ILO during a
      routine CLE test. Requirement for inclusion will be a CLE score ≥ 3. The primary endpoint
      will be the laryngeal response to maximal exercise, described quantitatively by a blinded
      observer using the CLE score system. Two CLE tests will be performed in each subject, one
      with - and one without - prior treatment with Atrovent. The patient will thus serve as
      her/his own control. Half the patients will receive Atrovent before the first study test (at
      T1), the other half before the second (at T2).

      The CLE-test

      The CLE-test was described in detail by the authors Heimdal et al. in the "Laryngoscope" in
      2006 and the scoring system by Maat et al. in the "European Archives of Otorhinolaryngology"
      in 2009. In short, the test combines a full cardio-pulmonary treadmill exercise set-up with
      continuous real-time transnasal video-laryngoscopy applied from rest to peak exercise to
      rest. A camera and a microphone placed in front of the subject enable recording of
      simultaneous video images of the external upper part of the body as well as recordings of the
      respiratory sounds. The subjects run on a treadmill according to a standardized protocol,
      incrementing speed and/or grade every minute with the aim to obtain peak oxygen consumption
      (peakVO2) after 6-12 min of exercise. The test is considered successful if the patient
      experience respiratory complaints, or indicate exhaustion, preferably supported by a plateau
      in oxygen consumption and/or the heart rate. All recordings continue until normal breathing
      is regained.

      The CLE-test scoring system was established based on evaluations of video recordings from
      both patients and symptom-negative controls who were examined with the CLE-test. The CLE-test
      scoring system encompasses separate assessments of the extent of medial rotation of the
      aryepiglottic folds and adduction of the vocal folds scored in representative respiratory
      cycles at two different points in time during the exercise session; i.e. at a moderate effort
      (when changing from walking to running on the treadmill) and at maximal effort (shortly
      before exhaustion). Adduction is graded from 0 (neutral position or abduction) to a maximum
      score of 3. This set-up establishes four sub-scores ranging from 0 to 3, i.e. glottic and
      supraglottic adduction at moderate (A and B), and maximal exercise (C and D). The sum score
      (E) may finally be categorized into three clusters: 0-2 (normal) and 3-4 (moderate) and 5 or
      more (severe).

      The study has been approved by the Western Norway Regional Committee for Medical and Health
      Research Ethics (REKVEST 2014/1885) and by the Norwegian Medicines Agency; European Union
      Drug Regulating Authorities Clinical Trials (EUDRACT) No. 2014-000302-34 (enclosed). The
      study will be performed under the guidance of the Paediatric Clinical Trial Unit at Haukeland
      University Hospital, a unit that has extensive experience in running clinical trials in
      children.
    

Intervention name(s): Ipratropium bromide spray
Intervention type(s): Drug
Intervention description(s): The patient will - or will not - receive Ipratropium bromide spray (MDI) 20 μg given through a plastic spacer two puffs 1 hour before a continuous laryngoscopy exercise test (CLE-test)
Other intervention name(s): Atrovent
Intervention MeSH terms: Bromides; Ipratropium
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Primary purpose: Treatment