Clinical Trial Details
— Status: Withdrawn
Administrative data
| NCT number |
NCT04402658 |
| Other study ID # |
NorwegianSSS2020 |
| Secondary ID |
|
| Status |
Withdrawn |
| Phase |
N/A
|
| First received |
|
| Last updated |
|
| Start date |
August 1, 2022 |
| Est. completion date |
December 20, 2023 |
Study information
| Verified date |
March 2022 |
| Source |
Norwegian School of Sport Sciences |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Interventional
|
Clinical Trial Summary
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.
Description:
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.
