<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT04402658</url>
  </required_header>
  <id_info>
    <org_study_id>NorwegianSSS2020</org_study_id>
    <nct_id>NCT04402658</nct_id>
  </id_info>
  <brief_title>Can Anti-asthmatic Medication Improve Sprint Performance in Healthy Endurance Athletes?</brief_title>
  <official_title>The Effect of Inhaled Salbutamol on Sprint Performance During and After Submaximal Endurance Exercise in Non-asthmatic Athletes</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Norwegian School of Sport Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Norwegian School of Sport Sciences</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The prevalence of asthma among athletes is higher than in the normal population and endurance&#xD;
      athletes are especially at increased risk. The gold standard for asthma treatment is inhaled&#xD;
      glucocorticoids with inhaled beta2 agonists before exercise and as a symptom relief. However,&#xD;
      the use of beta2 agonists in sports is debated because of potential performance-enhancing&#xD;
      effects and its use is regulated by the World Anti-Doping Agency (WADA).&#xD;
&#xD;
      The potential performance-enhancing effect of beta2 agonists on endurance performance and&#xD;
      sprint performance has each been investigated in several studies as it has been suspected&#xD;
      that non-asthmatic athletes use beta2 agonists for the purpose of improving performance. In&#xD;
      conclusion, beta2 agonists do not improve endurance athletic performance in the doses and&#xD;
      methods of use permitted by WADA. When it comes to anaerobic performance, the evidence is&#xD;
      currently non-conclusive as studies report conflicting effects. It is therefore conceivable&#xD;
      that beta2 agonists can improve the ability to sprint and increase power output during short&#xD;
      periods of high energy expenditure during an endurance competition. By testing such anaerobic&#xD;
      skills during endurance work in athletes, this study will provide valuable knowledge about&#xD;
      whether this drug may affect sports performance and will be of interest to WADA and anyone&#xD;
      else interested in fair play in sports.&#xD;
&#xD;
      The purpose of the project is to investigate whether the use of a WADA approved dose of&#xD;
      salbutamol (albuterol/Ventoline) has a performance-enhancing effect on sprint performance&#xD;
      during and after endurance work on an ergometer bike. Well-trained cyclists who do not have&#xD;
      asthma will perform two identical cycling protocols on two different days. The study is&#xD;
      designed as a double-blind cross-over study with placebo. Participants will perform multiple&#xD;
      30-second sprints during a standard submaximal effort to investigate the effect of salbutamol&#xD;
      on the maximum and average power of these sprints.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Theoretical background:&#xD;
&#xD;
      The use of beta2-agonists in sports is restricted due to possible performance enhancing&#xD;
      effects. The World Anti-Doping Agency's (WADA) prohibited list from January the 1st 2020&#xD;
      prohibits all use of beta2-agonists except inhaled salbutamol (maximum 1600 micrograms over&#xD;
      24 hours in divided doses not to exceed 800 micrograms over 12 hours starting from any dose),&#xD;
      inhaled formoterol (maximum delivered dose of 54 micrograms over 24 hours) and inhaled&#xD;
      salmeterol (maximum 200 micrograms over 24 hours).&#xD;
&#xD;
      Asthmatic athletes have consistently outperformed non-asthmatic athletes during the Olympic&#xD;
      Games, and the use of inhaled beta2-agonists by athletes is surrounded by controversy, which&#xD;
      have been highlighted in recent beta2-agonist anti-doping investigations involving&#xD;
      world-class athletes. In 2020, Riiser et al. completed two systematic reviews with&#xD;
      meta-analysis targeting the effect from beta2-agonists on aerobic (accepted in BSJM March&#xD;
      2020) and anaerobic (currently in review) performance. No effect was detected on aerobic&#xD;
      performance, however an effect on anaerobic performance was reported. However, these&#xD;
      meta-analyses separate the effects in either aerobic or anaerobic performance, while many&#xD;
      sports requires both a high aerobic and anaerobic performance to succeed. For example, the&#xD;
      development of endurance sports - such as cycling and cross-country skiing - has gone in a&#xD;
      direction where anaerobic abilities are gaining importance, such as during sprints at the&#xD;
      final stage of a race, closing gaps and during break away.&#xD;
&#xD;
      If beta2-agonists might improve performance in endurance sports through its effect on&#xD;
      anaerobic performance, studies that better simulate this aspect of an endurance competitions&#xD;
      is warranted. To the best of the present researcher's knowledge only three studies have&#xD;
      investigated this aspect and they yielded conflicting results. In 1988, Bedi et al. found&#xD;
      that competitive cyclists sprinted longer (196 sec vs 159 sec) after 60 min of cycling with a&#xD;
      single inhalation of salbutamol pre-ride as compared to placebo. Furthermore, higher fatigue&#xD;
      levels were reported during the final sprints after inhaling salbutamol, that may indicate a&#xD;
      better ability to perform all-out anaerobic effort. However, Altarawneh et al. (2016) found&#xD;
      no ergogenic effect of 1000 ug inhaled salbutamol on either continuous high-intensity (90 s&#xD;
      at 130 % V̇O2max) performance or multiple sprint performance (3 sets of 5x4 s sprint with 20&#xD;
      s break between sprints and 4.5 min serial break) in recreationally active men. Fitness level&#xD;
      has been suggested to confound the effect of beta2- agonists on physical performance, and to&#xD;
      the best of our knowledge no study has investigated the effect of a WADA approved dose of&#xD;
      inhaled salbutamol on measures of repeated bouts of anaerobic performance measured during&#xD;
      prolonged submaximal exercise in well trained athletes. Therefore, because of the potential&#xD;
      ergogenic effect of inhaled beta2-agonists on anaerobic performance combined with the&#xD;
      potential reduced VO2 during submaximal work reported by Bedi et al. (1988), the combination&#xD;
      of anaerobic performance and prolonged sub-maximal endurance exercise should be further&#xD;
      investigated.&#xD;
&#xD;
      Materials and methods:&#xD;
&#xD;
      Participants eligible to the study will be recruited from local cycle and triathlon clubs,&#xD;
      and sport high schools in the Oslo-area. The participants must be free from chest infection&#xD;
      for at least 4 weeks prior to assessment; and are not to be taking any medication and have no&#xD;
      other health or medical contradictions to them taking part in the study as confirm by&#xD;
      information provided on a physical activity readiness questionnaire.&#xD;
&#xD;
      Participants will visit the laboratory on three separate occasions. Participants will be&#xD;
      asked to prepare for each testing session in a similar manner and to refrain from caffeine&#xD;
      and alcohol consumption and heavy exercise for 24 hours before the experiment.&#xD;
&#xD;
      Experimental procedures:&#xD;
&#xD;
      On the first visit to the laboratory, height and weight will be measured, and participants&#xD;
      will fill out a physical activity readiness questionnaire before the test. Then the&#xD;
      participants will complete an incremental step exercises test on a bicycle ergometer (Lode,&#xD;
      Groningen, Netherlands) to establish the relationship between workload (W) and VO2. After a&#xD;
      warmup phase, the workload will then increase by 25 watts every 5th minute with a pedal&#xD;
      frequency of 90 revolutions per minute (rpm). During the last 3 min of each bout, VO2 (Oxycon&#xD;
      Pro, Jaeger GmbH, Hoechberg, Germany) and heart rate (HR) (Polar, Kempele, Finland) will be&#xD;
      measured. A capillary blood sample will be taken from a fingertip and analysed for blood&#xD;
      lactate concentration [La-] (Biosen C-line, EKF diagnostic GmbH, Magdeburg, Germany) and&#xD;
      glucose concentration [Glu] (HemoCue Glucose 201+, Ängholm, Sweden) after each 5 minutes bout&#xD;
      of cycling. The test will be terminated when the participants reach a [la-] level of ≥1.5&#xD;
      mmolˑL-1 above baseline [La-]. Linear regression analysis from the incremental step exercise&#xD;
      test will be used to determine the workload corresponding to 70% of VO2max for use on the&#xD;
      same bicycle ergometer in the subsequent experimental trials. Participants will then&#xD;
      immediately perform an incremental exercise test to determine VO2max. This test will start at&#xD;
      the work rate (W) in the second last 5-min bout for each participant and the work rate will&#xD;
      then be increased by 25 W each min, until exhaustion, defined as an inability to maintain&#xD;
      pedal cadence above 60 rpm. After 20 minutes of rest, participants will perform 30-second&#xD;
      Wingate tests for familiarisation purposes.&#xD;
&#xD;
      To exclude any participant with existing lung disease or asthma, the forced expiratory volume&#xD;
      in 1 s (FEV1) and forced vital capacity (FVC) will be measured by spirometry using maximum&#xD;
      expiratory flow volume loops (Oxycon Pro, Jaeger GmbH, Hoechberg, Germany) according to&#xD;
      European standard before and 0, 3, 5 and 10 minutes after the VO2max test. In addition, on&#xD;
      day 2 or 3 spirometry will be measured before and 15 minutes after inhalation of salbutamol&#xD;
      of which can identify subjects with a bronchoconstriction (with a cut off at Δ FEV1 of ≥12%&#xD;
      and 200 ml).&#xD;
&#xD;
      On day 2 and 3, identical protocols will be performed in randomized order as described&#xD;
      elsewhere.&#xD;
&#xD;
      Questionnaires On day 1, the subjects will fill out a questionnaire regarding the type,&#xD;
      duration, and intensity of training; exercise-related allergic and infectious symptoms;&#xD;
      social habits (smoking); drug and food supplements intake and antidoping regulations (15).&#xD;
      After each trial (day 2 and 3), participants will answer questions regarding respiratory&#xD;
      symptoms, common side effects, sensations of dyspnoea and muscle fatigue, and if they can&#xD;
      guess which intervention they received (salbutamol or placebo).&#xD;
&#xD;
      Statistical analyses Sample size is determined for the primary outcome &quot;mean power&quot; from the&#xD;
      Wingate tests, as described by Dell, Holleran &amp; Ramakrishnan (18). Effect size is based on&#xD;
      the study by Collomp et al. (19) who reported a difference in mean power of 51 W after&#xD;
      salbutamol (mean 585 +/- 27 W) vs placebo (534 +/- 35 W). Sample size calculations using an&#xD;
      online a priori power calculator (https://clincalc.com/stats/samplesize.aspx) revealed that&#xD;
      seven subjects in each group are necessary to obtain a power of 0.8 with a significance level&#xD;
      of 0.05, and. With the risk of dropouts and to ensure a high statistical power with a lower&#xD;
      salbutamol dose than in the study by Collomp et al., 20 participants will be included.&#xD;
&#xD;
      Two-way analyses of variance (ANOVA) for repeated measures will be used to evaluate the&#xD;
      statistical significance of the variables measured. A Tukey post hoc test will be used to&#xD;
      detect differences over time. A significance level (α) of 0.05 will be used.&#xD;
&#xD;
      Ethical considerations The study will be performed in accordance with the Declaration of&#xD;
      Helsinki. Before recruiting participants, the Regional Ethical Committee should evaluate and&#xD;
      approve the study. Written informed consent to take part will be obtained from participating&#xD;
      athletes. Except for possible discomfort with tachycardia or shakiness, participants will not&#xD;
      experience any expected side-effects.&#xD;
&#xD;
      Potential risks and benefits The investigators will include healthy, non-asthmatic&#xD;
      participants that will be pre-screened for asthma by medical history, use of medication and&#xD;
      lung function measured pre and post heavy exercise. The benefits of participation are that&#xD;
      the participants will acquire measurements of their VO2max and blood lactate concentration&#xD;
      during submaximal and maximal work which will be beneficial information for the athletes in&#xD;
      terms of exercise planning. The participants may experience known side effects of inhaled&#xD;
      salbutamol which include tremor, tachycardia, dry mouth, headache and muscle cramps (17).&#xD;
      Adverse events (AE) will be reported to the primary investigator and the standard routines of&#xD;
      the institution will be followed. This includes any event that is a result of a use error or&#xD;
      intentional misuse (from ISO/FDIS 14155): any untoward medical occurrence, unintended disease&#xD;
      or injury or any untoward clinical signs (including an abnormal laboratory finding) in&#xD;
      participants, or other persons, related to the procedures involved (any procedure in the&#xD;
      project plan).&#xD;
&#xD;
      Project responsibility and key roles The project will be carried out at the Norwegian School&#xD;
      of Sport Sciences in Oslo, which will be the institution with the academic responsibility.&#xD;
      Master students Martine Gøransson and Sandra Viksjø will perform the tests, under supervision&#xD;
      by PhD Julie Stang, PhD Olav Vikmoen and PhD student Ove H Sollie. Prof. Thomas Halvorsen&#xD;
      (MD) is medical responsible for the project. Professor Trine Stensrud and PhD Elisabeth&#xD;
      Edvardsen are associate researchers in the project.&#xD;
&#xD;
      Data management Procedures for data management will be implemented according to the data&#xD;
      processing routines at the Norwegian School of Sport Sciences and conducted according to&#xD;
      standards of GCP. During the course of the study, the key investigators will have access to&#xD;
      the study material, which will be secured by a data professional officer (DPO). Data will be&#xD;
      de-identified and stored in a secured database. A Subject Identification List, with cross&#xD;
      reference between the subject's identification number in the study and the subject's personal&#xD;
      data, will be kept looked away with the study documentation. Only the key researchers will&#xD;
      have access to this code book with the link between participant ID and data. Database&#xD;
      cleaning and issuing data queries will be traceable and transparent with logs. Retention&#xD;
      period for data storage is 5 years. Participating investigators will be responsible for data&#xD;
      collection, data processing and report writing.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Problem with acquiring study medication and lack of resources.&#xD;
  </why_stopped>
  <start_date type="Anticipated">August 1, 2022</start_date>
  <completion_date type="Anticipated">December 20, 2023</completion_date>
  <primary_completion_date type="Anticipated">May 30, 2023</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <intervention_model_description>The present study has a double-blinded and randomized cross-over design with participants visiting the laboratory on three separate occasions. The purpose of the first visit is to familiarize the participant with the equipment and the exercise performance protocol as well as to assess physiologic exercise data that will be used to determine the power output of the endurance exercise protocol on visits two and three. For a given participant, trials on day two and three will be conducted in randomized order, on the same time of day, and separated by more than 72 hours to ensure complete wash-out of salbutamol, and less than three weeks. The randomization will be performed using a computer random number generator.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
    <masking_description>Both participants and key study personnel will be blinded for the intervention as an external person will provide the participant with sequentially numbered drug containers of identical appearance, for salbutamol and placebo, respectively.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Anaerobic performance</measure>
    <time_frame>Differences between experimental trial and placebo trial at 15 minutes</time_frame>
    <description>Measures as mean power (Watts) from the 30-second Wingate tests carried out on an ergometer cycle.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Anaerobic performance</measure>
    <time_frame>Differences between experimental trial and placebo trial at 30 minutes</time_frame>
    <description>Measures as mean power (Watts) from the 30-second Wingate tests carried out on an ergometer cycle.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Sprint performance</measure>
    <time_frame>Differences between experimental trial and placebo trial at 60 minutes</time_frame>
    <description>Mean power (Watts) during an all-out sprint on an ergometer cycle.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume in 1 second (FEV1)</measure>
    <time_frame>Change from baseline FEV1 at 15 minutes</time_frame>
    <description>Measurements of lung function by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume in 1 second (FEV1)</measure>
    <time_frame>Change from baseline FEV1 at 30 minutes</time_frame>
    <description>Measurements of lung function by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Forced expiratory volume in 1 second (FEV1)</measure>
    <time_frame>Difference from placebo trial at 30 minutes</time_frame>
    <description>Measurements of lung function by spirometry</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate (btp)</measure>
    <time_frame>Change from baseline heart rate at 15 minutes</time_frame>
    <description>Heart rate measured by a Polar Chest-strap</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate (btp)</measure>
    <time_frame>Change from baseline heart rate at 30 minutes</time_frame>
    <description>Heart rate measured by a Polar Chest-strap</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Heart rate (btp)</measure>
    <time_frame>Difference from placebo trial at 30 minutes</time_frame>
    <description>Heart rate measured by a Polar Chest-strap</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Sports Drug Abuse</condition>
  <arm_group>
    <arm_group_label>Physical performance test</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>After performing measurements of lung function by spirometry, participants will inhale either salbutamol or placebo. After 15 minutes of rest, a second spirometry will be performed before the participants warm-up by 10 minutes cycling. The exercise protocol will consist of 60 minutes of cycling at 70% of maximal oxygen consumption (VO2max) on the cycle ergometer followed by an all-out sprint. Several times during the exercise test, 30-second Wingate tests will be conducted. Participants will be blinded to feedback such as power (W), distance covered, and heart rate. Strong verbal encouragement will be given to each participant for them to perform their best. Measurements of lung function (spirometry), heart rate, arterial oxygen saturation and Borg ratings of perceived exercising will be recorded throughout the trials, as well as capillary blood sampled for analysis of [La-] and [Glucose].</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Inhaled salbutamol</intervention_name>
    <description>Participants will inhale 800 μg salbutamol (or placebo) using a standard metered dose inhaler used for asthma treatment, and a standard spacer device will be used to allow optimal delivery of the drug to the lung. The inhaler delivers 100 μg of salbutamol with each actuation (i.e., 8 puffs/actuations gives 800 μg) with inhalation time being approximately ~2 min (10 breaths) and the manufacturer's user instructions will be followed. Although complete uptake of salbutamol cannot be concluded as any salbutamol left in the spacer, mouth or remaining in the lung will be not measured. This dose of Salbutamol is chosen because it is the highest dose permitted by the World Anti Doping Agency (WADA).</description>
    <arm_group_label>Physical performance test</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  well trained cyclists and triathletes (VO2max in mLˑkg-1ˑmin-1 ≥ 65 male/55 female)&#xD;
             who are actively engaged in endurance cycling training at least 4 times per week.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  a doctor diagnosed asthma and/or the use of anti-asthmatic medications the last 12&#xD;
             months prior to participation.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Julie S Stang, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Norwegian School of Sport Sciences</affiliation>
  </overall_official>
  <verification_date>March 2022</verification_date>
  <study_first_submitted>April 29, 2020</study_first_submitted>
  <study_first_submitted_qc>May 20, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">May 27, 2020</study_first_posted>
  <last_update_submitted>March 9, 2022</last_update_submitted>
  <last_update_submitted_qc>March 9, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">March 25, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Norwegian School of Sport Sciences</investigator_affiliation>
    <investigator_full_name>Julie Stang</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <keyword>Anaerobic performance</keyword>
  <keyword>Athletes</keyword>
  <keyword>Doping</keyword>
  <keyword>Asthma</keyword>
  <keyword>Endurance sports</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Substance-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Albuterol</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT04402658
org study id: NorwegianSSS2020
nct id: NCT04402658
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
is us export: No
The prevalence of asthma among athletes is higher than in the normal population and endurance
      athletes are especially at increased risk. The gold standard for asthma treatment is inhaled
      glucocorticoids with inhaled beta2 agonists before exercise and as a symptom relief. However,
      the use of beta2 agonists in sports is debated because of potential performance-enhancing
      effects and its use is regulated by the World Anti-Doping Agency (WADA).

      The potential performance-enhancing effect of beta2 agonists on endurance performance and
      sprint performance has each been investigated in several studies as it has been suspected
      that non-asthmatic athletes use beta2 agonists for the purpose of improving performance. In
      conclusion, beta2 agonists do not improve endurance athletic performance in the doses and
      methods of use permitted by WADA. When it comes to anaerobic performance, the evidence is
      currently non-conclusive as studies report conflicting effects. It is therefore conceivable
      that beta2 agonists can improve the ability to sprint and increase power output during short
      periods of high energy expenditure during an endurance competition. By testing such anaerobic
      skills during endurance work in athletes, this study will provide valuable knowledge about
      whether this drug may affect sports performance and will be of interest to WADA and anyone
      else interested in fair play in sports.

      The purpose of the project is to investigate whether the use of a WADA approved dose of
      salbutamol (albuterol/Ventoline) has a performance-enhancing effect on sprint performance
      during and after endurance work on an ergometer bike. Well-trained cyclists who do not have
      asthma will perform two identical cycling protocols on two different days. The study is
      designed as a double-blind cross-over study with placebo. Participants will perform multiple
      30-second sprints during a standard submaximal effort to investigate the effect of salbutamol
      on the maximum and average power of these sprints.
Theoretical background:

      The use of beta2-agonists in sports is restricted due to possible performance enhancing
      effects. The World Anti-Doping Agency's (WADA) prohibited list from January the 1st 2020
      prohibits all use of beta2-agonists except inhaled salbutamol (maximum 1600 micrograms over
      24 hours in divided doses not to exceed 800 micrograms over 12 hours starting from any dose),
      inhaled formoterol (maximum delivered dose of 54 micrograms over 24 hours) and inhaled
      salmeterol (maximum 200 micrograms over 24 hours).

      Asthmatic athletes have consistently outperformed non-asthmatic athletes during the Olympic
      Games, and the use of inhaled beta2-agonists by athletes is surrounded by controversy, which
      have been highlighted in recent beta2-agonist anti-doping investigations involving
      world-class athletes. In 2020, Riiser et al. completed two systematic reviews with
      meta-analysis targeting the effect from beta2-agonists on aerobic (accepted in BSJM March
      2020) and anaerobic (currently in review) performance. No effect was detected on aerobic
      performance, however an effect on anaerobic performance was reported. However, these
      meta-analyses separate the effects in either aerobic or anaerobic performance, while many
      sports requires both a high aerobic and anaerobic performance to succeed. For example, the
      development of endurance sports - such as cycling and cross-country skiing - has gone in a
      direction where anaerobic abilities are gaining importance, such as during sprints at the
      final stage of a race, closing gaps and during break away.

      If beta2-agonists might improve performance in endurance sports through its effect on
      anaerobic performance, studies that better simulate this aspect of an endurance competitions
      is warranted. To the best of the present researcher's knowledge only three studies have
      investigated this aspect and they yielded conflicting results. In 1988, Bedi et al. found
      that competitive cyclists sprinted longer (196 sec vs 159 sec) after 60 min of cycling with a
      single inhalation of salbutamol pre-ride as compared to placebo. Furthermore, higher fatigue
      levels were reported during the final sprints after inhaling salbutamol, that may indicate a
      better ability to perform all-out anaerobic effort. However, Altarawneh et al. (2016) found
      no ergogenic effect of 1000 ug inhaled salbutamol on either continuous high-intensity (90 s
      at 130 % V̇O2max) performance or multiple sprint performance (3 sets of 5x4 s sprint with 20
      s break between sprints and 4.5 min serial break) in recreationally active men. Fitness level
      has been suggested to confound the effect of beta2- agonists on physical performance, and to
      the best of our knowledge no study has investigated the effect of a WADA approved dose of
      inhaled salbutamol on measures of repeated bouts of anaerobic performance measured during
      prolonged submaximal exercise in well trained athletes. Therefore, because of the potential
      ergogenic effect of inhaled beta2-agonists on anaerobic performance combined with the
      potential reduced VO2 during submaximal work reported by Bedi et al. (1988), the combination
      of anaerobic performance and prolonged sub-maximal endurance exercise should be further
      investigated.

      Materials and methods:

      Participants eligible to the study will be recruited from local cycle and triathlon clubs,
      and sport high schools in the Oslo-area. The participants must be free from chest infection
      for at least 4 weeks prior to assessment; and are not to be taking any medication and have no
      other health or medical contradictions to them taking part in the study as confirm by
      information provided on a physical activity readiness questionnaire.

      Participants will visit the laboratory on three separate occasions. Participants will be
      asked to prepare for each testing session in a similar manner and to refrain from caffeine
      and alcohol consumption and heavy exercise for 24 hours before the experiment.

      Experimental procedures:

      On the first visit to the laboratory, height and weight will be measured, and participants
      will fill out a physical activity readiness questionnaire before the test. Then the
      participants will complete an incremental step exercises test on a bicycle ergometer (Lode,
      Groningen, Netherlands) to establish the relationship between workload (W) and VO2. After a
      warmup phase, the workload will then increase by 25 watts every 5th minute with a pedal
      frequency of 90 revolutions per minute (rpm). During the last 3 min of each bout, VO2 (Oxycon
      Pro, Jaeger GmbH, Hoechberg, Germany) and heart rate (HR) (Polar, Kempele, Finland) will be
      measured. A capillary blood sample will be taken from a fingertip and analysed for blood
      lactate concentration [La-] (Biosen C-line, EKF diagnostic GmbH, Magdeburg, Germany) and
      glucose concentration [Glu] (HemoCue Glucose 201+, Ängholm, Sweden) after each 5 minutes bout
      of cycling. The test will be terminated when the participants reach a [la-] level of ≥1.5
      mmolˑL-1 above baseline [La-]. Linear regression analysis from the incremental step exercise
      test will be used to determine the workload corresponding to 70% of VO2max for use on the
      same bicycle ergometer in the subsequent experimental trials. Participants will then
      immediately perform an incremental exercise test to determine VO2max. This test will start at
      the work rate (W) in the second last 5-min bout for each participant and the work rate will
      then be increased by 25 W each min, until exhaustion, defined as an inability to maintain
      pedal cadence above 60 rpm. After 20 minutes of rest, participants will perform 30-second
      Wingate tests for familiarisation purposes.

      To exclude any participant with existing lung disease or asthma, the forced expiratory volume
      in 1 s (FEV1) and forced vital capacity (FVC) will be measured by spirometry using maximum
      expiratory flow volume loops (Oxycon Pro, Jaeger GmbH, Hoechberg, Germany) according to
      European standard before and 0, 3, 5 and 10 minutes after the VO2max test. In addition, on
      day 2 or 3 spirometry will be measured before and 15 minutes after inhalation of salbutamol
      of which can identify subjects with a bronchoconstriction (with a cut off at Δ FEV1 of ≥12%
      and 200 ml).

      On day 2 and 3, identical protocols will be performed in randomized order as described
      elsewhere.

      Questionnaires On day 1, the subjects will fill out a questionnaire regarding the type,
      duration, and intensity of training; exercise-related allergic and infectious symptoms;
      social habits (smoking); drug and food supplements intake and antidoping regulations (15).
      After each trial (day 2 and 3), participants will answer questions regarding respiratory
      symptoms, common side effects, sensations of dyspnoea and muscle fatigue, and if they can
      guess which intervention they received (salbutamol or placebo).

      Statistical analyses Sample size is determined for the primary outcome "mean power" from the
      Wingate tests, as described by Dell, Holleran & Ramakrishnan (18). Effect size is based on
      the study by Collomp et al. (19) who reported a difference in mean power of 51 W after
      salbutamol (mean 585 +/- 27 W) vs placebo (534 +/- 35 W). Sample size calculations using an
      online a priori power calculator (https://clincalc.com/stats/samplesize.aspx) revealed that
      seven subjects in each group are necessary to obtain a power of 0.8 with a significance level
      of 0.05, and. With the risk of dropouts and to ensure a high statistical power with a lower
      salbutamol dose than in the study by Collomp et al., 20 participants will be included.

      Two-way analyses of variance (ANOVA) for repeated measures will be used to evaluate the
      statistical significance of the variables measured. A Tukey post hoc test will be used to
      detect differences over time. A significance level (α) of 0.05 will be used.

      Ethical considerations The study will be performed in accordance with the Declaration of
      Helsinki. Before recruiting participants, the Regional Ethical Committee should evaluate and
      approve the study. Written informed consent to take part will be obtained from participating
      athletes. Except for possible discomfort with tachycardia or shakiness, participants will not
      experience any expected side-effects.

      Potential risks and benefits The investigators will include healthy, non-asthmatic
      participants that will be pre-screened for asthma by medical history, use of medication and
      lung function measured pre and post heavy exercise. The benefits of participation are that
      the participants will acquire measurements of their VO2max and blood lactate concentration
      during submaximal and maximal work which will be beneficial information for the athletes in
      terms of exercise planning. The participants may experience known side effects of inhaled
      salbutamol which include tremor, tachycardia, dry mouth, headache and muscle cramps (17).
      Adverse events (AE) will be reported to the primary investigator and the standard routines of
      the institution will be followed. This includes any event that is a result of a use error or
      intentional misuse (from ISO/FDIS 14155): any untoward medical occurrence, unintended disease
      or injury or any untoward clinical signs (including an abnormal laboratory finding) in
      participants, or other persons, related to the procedures involved (any procedure in the
      project plan).

      Project responsibility and key roles The project will be carried out at the Norwegian School
      of Sport Sciences in Oslo, which will be the institution with the academic responsibility.
      Master students Martine Gøransson and Sandra Viksjø will perform the tests, under supervision
      by PhD Julie Stang, PhD Olav Vikmoen and PhD student Ove H Sollie. Prof. Thomas Halvorsen
      (MD) is medical responsible for the project. Professor Trine Stensrud and PhD Elisabeth
      Edvardsen are associate researchers in the project.

      Data management Procedures for data management will be implemented according to the data
      processing routines at the Norwegian School of Sport Sciences and conducted according to
      standards of GCP. During the course of the study, the key investigators will have access to
      the study material, which will be secured by a data professional officer (DPO). Data will be
      de-identified and stored in a secured database. A Subject Identification List, with cross
      reference between the subject's identification number in the study and the subject's personal
      data, will be kept looked away with the study documentation. Only the key researchers will
      have access to this code book with the link between participant ID and data. Database
      cleaning and issuing data queries will be traceable and transparent with logs. Retention
      period for data storage is 5 years. Participating investigators will be responsible for data
      collection, data processing and report writing.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: The present study has a double-blinded and randomized cross-over design with participants visiting the laboratory on three separate occasions. The purpose of the first visit is to familiarize the participant with the equipment and the exercise performance protocol as well as to assess physiologic exercise data that will be used to determine the power output of the endurance exercise protocol on visits two and three. For a given participant, trials on day two and three will be conducted in randomized order, on the same time of day, and separated by more than 72 hours to ensure complete wash-out of salbutamol, and less than three weeks. The randomization will be performed using a computer random number generator.
primary purpose: Basic Science
masking: None (Open Label)
masking description: Both participants and key study personnel will be blinded for the intervention as an external person will provide the participant with sequentially numbered drug containers of identical appearance, for salbutamol and placebo, respectively.
measure: Anaerobic performance
time frame: Differences between experimental trial and placebo trial at 15 minutes
description: Measures as mean power (Watts) from the 30-second Wingate tests carried out on an ergometer cycle.
measure: Anaerobic performance
time frame: Differences between experimental trial and placebo trial at 30 minutes
description: Measures as mean power (Watts) from the 30-second Wingate tests carried out on an ergometer cycle.
measure: Sprint performance
time frame: Differences between experimental trial and placebo trial at 60 minutes
description: Mean power (Watts) during an all-out sprint on an ergometer cycle.
measure: Forced expiratory volume in 1 second (FEV1)
time frame: Change from baseline FEV1 at 15 minutes
description: Measurements of lung function by spirometry
measure: Forced expiratory volume in 1 second (FEV1)
time frame: Change from baseline FEV1 at 30 minutes
description: Measurements of lung function by spirometry
measure: Forced expiratory volume in 1 second (FEV1)
time frame: Difference from placebo trial at 30 minutes
description: Measurements of lung function by spirometry
measure: Heart rate (btp)
time frame: Change from baseline heart rate at 15 minutes
description: Heart rate measured by a Polar Chest-strap
measure: Heart rate (btp)
time frame: Change from baseline heart rate at 30 minutes
description: Heart rate measured by a Polar Chest-strap
measure: Heart rate (btp)
time frame: Difference from placebo trial at 30 minutes
description: Heart rate measured by a Polar Chest-strap
arm group label: Physical performance test
arm group type: Experimental
description: After performing measurements of lung function by spirometry, participants will inhale either salbutamol or placebo. After 15 minutes of rest, a second spirometry will be performed before the participants warm-up by 10 minutes cycling. The exercise protocol will consist of 60 minutes of cycling at 70% of maximal oxygen consumption (VO2max) on the cycle ergometer followed by an all-out sprint. Several times during the exercise test, 30-second Wingate tests will be conducted. Participants will be blinded to feedback such as power (W), distance covered, and heart rate. Strong verbal encouragement will be given to each participant for them to perform their best. Measurements of lung function (spirometry), heart rate, arterial oxygen saturation and Borg ratings of perceived exercising will be recorded throughout the trials, as well as capillary blood sampled for analysis of [La-] and [Glucose].
intervention type: Drug
intervention name: Inhaled salbutamol
description: Participants will inhale 800 μg salbutamol (or placebo) using a standard metered dose inhaler used for asthma treatment, and a standard spacer device will be used to allow optimal delivery of the drug to the lung. The inhaler delivers 100 μg of salbutamol with each actuation (i.e., 8 puffs/actuations gives 800 μg) with inhalation time being approximately ~2 min (10 breaths) and the manufacturer's user instructions will be followed. Although complete uptake of salbutamol cannot be concluded as any salbutamol left in the spacer, mouth or remaining in the lung will be not measured. This dose of Salbutamol is chosen because it is the highest dose permitted by the World Anti Doping Agency (WADA).
arm group label: Physical performance test
criteria: 
gender: All
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Julie S Stang, PhD
role: Principal Investigator
affiliation: Norwegian School of Sport Sciences
responsible party type: Principal Investigator
investigator affiliation: Norwegian School of Sport Sciences
investigator full name: Julie Stang
investigator title: Principal Investigator
mesh term: Substance-Related Disorders
mesh term: Albuterol
sharing ipd: No