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    Clinical Trial Results:
    Mestinon and Salbutamol Tolerability and Efficacy as therapy for Post-COVID-19 Myopathy - A randomized, placebo-controlled, rater and subject-blinded, 2x2 crossover study.

    Summary
    EudraCT number
    		 2021-002610-14
    Trial protocol
    		 DK  
    Global end of trial date
    30 Apr 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jan 2026
    First version publication date
    02 Jan 2026
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    79835
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aarhus University Hospital
    Sponsor organisation address
    Palle Juul-Jensens Boulevard 99, Aarhus N, Denmark, 8200
    Public contact
    Research assistant Atle Vigild Lomstein, Aarhus University Hospital, Deparment of Neurology, 45 28, atllom@rm.dk
    Scientific contact
    Sponsor Professor Henning Andersen, Aarhus University Hospital, Deparment of Neurology, 45 7845 4250, hennande@rm.dk
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    11 Sep 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    30 Apr 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Apr 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Determining tolerability and efficacy of Salbutamol as treatment for Post-COVID-19 myopathy without neuromuscular transmission defect. Determining tolerability and efficacy of Salbutamol and Mestinon as treatments for Post-COVID-19 myopathy with neuromuscular transmission defect.
    Protection of trial subjects
    The study is conducted in compliance with ICH GCP E6 (R2). The project was monitored according to guidelines of Good Clinical practice by GCP-coordinator, GCP-unit Aalborg and Aarhus University Hospitals. Study data and information will be stored and handled in accordance to local/national laws and regulations. The study apply to the specifications of GDPR. Written and oral information concerning the present trial was provided. Adequate time to consideration was provided (up to 30 days). Prior to any study related procedures, a signed informed consent form was obtained. History of heart disease, diabetes or any other illness putting a participant at risk when treated with study drugs were exclusion criteria. Moderate or severe hypertension, ecg-abnormalities, thyroid disease or diabetes discovered discovered at screening led to exclusion. Any adverse reaction deemed too distressful or potentially harmful let to termination of participation by sponsor and investigator. Participants were screened with ecg and blood pressure measurement at every visit and screened for adverse events. The doses of the study drugs were within a normally well tolerated level and the study drugs are thouroughly tested and, in general, well tolerated.
    Background therapy
    		 None
    Evidence for comparator
    		 The β2-adrenergic agonist Salbutamol registered for treatment of asthma is also known to increase muscle strength and endurance in healthy individuals. It’s use as a doping agent in professional cycling is well known and the effects of the drug has been demonstrated in multiple clinical studies. Physiologically, Salbutamol is thought to increase T3-levels and post-exercise Growth Hormone (GH) levels after few weeks of treatment and induce muscular growth and increased contractility after longer treatment regimens. Salbutamol is well tolerated and increasingly used as an established treatment in neuromuscular disorders like congenital myasthenic syndrome as well as we have had promising experiences for its use in autoimmune myasthenia gravis in a currently running trial (NCT number: NCT03914638) and for off label use in our Neurology Clinic at AUH. Pyridostigmine (Mestinon) is the preferred first-line symptomatic treatment for myasthenia gravis. Mestinon increases the availability of acetylcholine outside the nervous system. The reduced amount of accessible nicotinic acetylcholine-receptors in the neuromuscular junction is counteracted by increased availability of the ligand, reducing symptoms of muscle weakness and fatigability. The mechanisms behind long-term fatigue, muscle weakness, and exercise intolerance in post COVID-19 patients are unknown, but our experiences indicate that myopathy and neuromuscular transmission dysfunction is prominent. Salbutamol and Mestinon is known to improve disability in disorders with similar symptoms.
    Actual start date of recruitment
    01 Oct 2021
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 45
    Worldwide total number of subjects
    45
    EEA total number of subjects
    45
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    45
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Long COVID-19 patients from Northern Region, Central Region and Sourthern Region in Denmark. Possible candidates were examined at the Department of Neurology and referred to EMG. A pre-screening was conducted and patients elligible for inclusion were invited to screening. Screening was initiated nov. 11th 2021 and last screening was dec 19th 2023

    Pre-assignment
    Screening details
    		 Adults age 18-65 with fatigue after COVID-19 infection for at least 3 months with either abnormal EMG-findings or proximal weakness. 147 evaluated for screening and 45 invited and passes screening. 2 weeks of run-in before initiation of study drug.

    Period 1
    Period 1 title
    Treatment period
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    Both study drug and Placebo tablets was encapsulated in gelatin-capsules and looked identical. Neither investigator, rater nor subject knew whether contents are active or placebo. Subjects were randomized through computer-based randomization software at Hospitalsapoteket. Randomization envelopes were supplied by Hospitalsapoteket and sealed until end of trial was confirmed and approved by GCP-monitor.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Active treatment Arm A
    Arm description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect. Active treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pyridostigmine
    Investigational medicinal product code
    N07AA02
    Other name
    Mestinon
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg, 3 times daily, oral ingestion

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    R03CC02
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg, 3 times daily, ingested orally

    Arm title
    		 Active treatment Arm B
    Arm description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination. Active treatment period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    R03CC02
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg, 3 times daily, ingested orally

    Arm title
    		 Placebo Arm A
    Arm description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect. Placebo period. Placebo ressembles mestinon and salbutamol treatment in active treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Place capsules ressembling active treatment.

    Arm title
    		 Placebo Arm B
    Arm description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination. Placebo period. Placebo ressembles salbutmol from active treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo capsule

    Number of subjects in period 1
    		Active treatment Arm A Active treatment Arm B Placebo Arm A Placebo Arm B
    Started
    24
    21
    24
    21
    Wash-out after week 6
    23
    20
    24
    21
    Completed
    23
    20
    24
    21
    Not completed
    1
    1
    0
    0
         Physician decision
    1
    -
    -
    -
         Consent withdrawn by subject
    -
    1
    -
    -
    Period 2
    Period 2 title
    Run-in screening period
    Is this the baseline period?
    		 Yes [1]
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Both study drug and Placebo tablets was encapsulated in gelatin-capsules and looked identical. Neither investigator, rater nor subject knew whether contents are active or placebo. Subjects were randomized through computer-based randomization software at Hospitalsapoteket. Randomization envelopes were supplied by Hospitalsapoteket and sealed until end of trial was confirmed and approved by GCP-monitor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Arm A
    Arm description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Pyridostigmine
    Investigational medicinal product code
    N07AA02
    Other name
    Mestinon
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    60 mg, 3 times daily, oral ingestion

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    R03CC02
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg, 3 times daily, ingested orally

    Arm title
    		 Arm B
    Arm description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Salbutamol
    Investigational medicinal product code
    R03CC02
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    4 mg, 3 times daily, ingested orally

    Notes
    [1] - Period 1 is not the baseline period. It is expected that period 1 will be the baseline period.
    Justification: It is in accordance with the protocol
    Number of subjects in period 2
    		Arm A Arm B
    Started
    24
    21
    Completed
    24
    21

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Arm A
    Reporting group description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect.

    Reporting group title
    Arm B
    Reporting group description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination.

    Reporting group values
    		 Arm A Arm B Total
    Number of subjects
    		 24 21 45
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 24 21 45
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Age continuous
    Group A, age at inclusion
    Units: years
        arithmetic mean (standard deviation)
    		 52.6 ( 9.65 ) 45.2 ( 9.23 ) -
    Gender categorical
    Units: Subjects
        Female
    		 16 16 32
        Male
    		 8 5 13
    Subject analysis sets

    Subject analysis set title
    Per protocol analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects adhering to procotol and treatment periods.

    Subject analysis sets values
    		 Per protocol analysis
    Number of subjects
    45
    Age categorical
    Units: Subjects
        In utero
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
        Newborns (0-27 days)
    0
        Infants and toddlers (28 days-23 months)
    0
        Children (2-11 years)
    0
        Adolescents (12-17 years)
    0
        Adults (18-64 years)
    45
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Group A, age at inclusion
    Units: years
        arithmetic mean (standard deviation)
    49.1 ( 10.1 )
    Gender categorical
    Units: Subjects
        Female
    32
        Male
    13

    End points

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    End points reporting groups
    Reporting group title
    Active treatment Arm A
    Reporting group description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect. Active treatment period.

    Reporting group title
    Active treatment Arm B
    Reporting group description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination. Active treatment period.

    Reporting group title
    Placebo Arm A
    Reporting group description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect. Placebo period. Placebo ressembles mestinon and salbutamol treatment in active treatment period.

    Reporting group title
    Placebo Arm B
    Reporting group description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination. Placebo period. Placebo ressembles salbutmol from active treatment period.
    Reporting group title
    Arm A
    Reporting group description
    		 Participants with abnormal jitter on EMG suggesting neuromuscular transmission defect.

    Reporting group title
    Arm B
    Reporting group description
    		 Subjects included did not have abnormal jitter in single fiber EMG. Instead, participants included had either myopathic changes in the EMG or proximal weakness upon physical neurological examination.

    Subject analysis set title
    Per protocol analysis
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All subjects adhering to procotol and treatment periods.

    Primary: Neuro QoL Fatigue

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    End point title
    		 Neuro QoL Fatigue
    End point description
    Primary efficacy parameter is improvement of fatigue as assessed by patient reported outcome (PRO). The Neuro QOL fatigue scale is a patient reported outcome used to rate fatigue and impact on quality of life. Investigations in neuromuscular disease show that Neuro-QOL correlate with disease severity and quality of life, and can improve after treatment. Neuro-QOL fatigue scale consists of 19 items rated on a scale from 1-5. From the total score, a T-score is calculated from 0-100. A T-score of 50 represents the mean score found in validation studies among a healthy population of American subjects. A T-score increase of 10 represents an increase of one standard deviation (translating to more fatigue) and a decrease of 10 represents a decrease of one standard deviation (translating to less fatigue).
    End point type
    Primary
    End point timeframe
    Before and after each of the treatment periods. Expressed as a mean difference in change in fatigue score before and after treatment with placebo compared to treatment with study drug.
    End point values
    		 Active treatment Arm A Active treatment Arm B
    Number of subjects analysed
    15
    19
    Units: Index
        median (standard deviation)
    -1.87 ( 7.32 )
    -3.11 ( 8.93 )
    Statistical analysis title
    		 Results NeuroQOL
    Statistical analysis description
    If patients had missing data at visit 2, data from visit 1 (screening) was used if available. Change in endpoint during active and placebo periods were calculated as absolute difference (start-of-period-visit subtracted from end-of-period-visit). Difference in change during periods (effect of treatment) were assessed as absolute differences by paired t-test. Assumptions hereof were checked by visual inspection of Bland-Altman plot and Q-Q plot of the difference.
    Comparison groups
    Active treatment Arm A v Active treatment Arm B
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.87
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.92
         upper limit
    		 2.19
    Notes
    [1] - Comparison of reporting group 1 (Active treatment group A) and reporting group 3 (placebo group A)
    Statistical analysis title
    		 Results NeuroQOL
    Statistical analysis description
    If patients had missing data at visit 2, data from visit 1 (screening) was used if available. Change in endpoint during active and placebo periods were calculated as absolute difference (start-of-period-visit subtracted from end-of-period-visit). Difference in change during periods (effect of treatment) were assessed as absolute differences by paired t-test. Assumptions hereof were checked by visual inspection of Bland-Altman plot and Q-Q plot of the difference.
    Comparison groups
    Active treatment Arm B v Active treatment Arm A
    Number of subjects included in analysis
    34
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.11
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -7.41
         upper limit
    		 1.2
    Notes
    [2] - Comparison of reporting group 2 (active treatment group B) and reporting group 4 (placebo group B)

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    All AEs/ARs that occur during the trial were recorded
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 unknown
    Dictionary version
    0
    Reporting groups
    Reporting group title
    Group A
    Reporting group description
    		 -

    Reporting group title
    Group B
    Reporting group description
    		 -

    Serious adverse events
    		 Group A Group B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 21 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Group A Group B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    24 / 24 (100.00%)
    21 / 21 (100.00%)
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    14 / 24 (58.33%)
    11 / 21 (52.38%)
         occurrences all number
    14
    11
    Tremor
         subjects affected / exposed
    16 / 24 (66.67%)
    15 / 21 (71.43%)
         occurrences all number
    16
    15
    Dizziness
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    General disorders and administration site conditions
    Headache
         subjects affected / exposed
    5 / 24 (20.83%)
    6 / 21 (28.57%)
         occurrences all number
    5
    6
    Mucosal dryness
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Toothache
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Constipation
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Nausea
         subjects affected / exposed
    1 / 24 (4.17%)
    1 / 21 (4.76%)
         occurrences all number
    1
    1
    Diarrhoea
         subjects affected / exposed
    5 / 24 (20.83%)
    1 / 21 (4.76%)
         occurrences all number
    5
    1
    Heartburn
         subjects affected / exposed
    1 / 24 (4.17%)
    2 / 21 (9.52%)
         occurrences all number
    1
    2
    Dyspepsia
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Burning sensation
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Sweating
         subjects affected / exposed
    4 / 24 (16.67%)
    3 / 21 (14.29%)
         occurrences all number
    4
    3
    Edema
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Hematoma
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Renal and urinary disorders
    Urge incontinence
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 21 (4.76%)
         occurrences all number
    2
    1
    Musculoskeletal and connective tissue disorders
    Muscle spasms
         subjects affected / exposed
    13 / 24 (54.17%)
    7 / 21 (33.33%)
         occurrences all number
    13
    7
    Infections and infestations
    cold
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0
    Herpes genitalis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 21 (4.76%)
         occurrences all number
    0
    1
    Metabolism and nutrition disorders
    Weight loss poor
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 21 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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