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    Clinical Trial Results:
    Botulinum toxin type A as treatment for chronic myogenous orofacial pain - a radomized controlled, double-blind clinical trial

    Summary
    EudraCT number
    		 2021-002784-21
    Trial protocol
    		 SE  
    Global end of trial date
    18 Jan 2024

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2024
    First version publication date
    15 Dec 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    20210516
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Västra Götalandsregionen
    Sponsor organisation address
    Biskopsbogatan 27, Mölndal, Sweden, 43180
    Public contact
    Institute of odontology, Sahlgrenska Academy at the University of Gotheburg, +46 317860000, info@odontologi.gu.se
    Scientific contact
    Institute of odontology, Sahlgrenska Academy at the University of Gotheburg, +46 317860000, info@odontologi.gu.se
    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
    18 Jan 2024
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Jan 2024
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Jan 2024
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Evaluate whether botulinum toxin A provides a significantly better pain-relieving effect for patients with orofacial myalgia compared to saline up to 6 months via evaluation of subjective perception of pain reduction and number of millimeters of pain free mouth opening.
    Protection of trial subjects
    Patients were well informed verbally and in writing about possible side effects. All procedures followed good clinical standard and hygene. Staff handling botulinumtoxin A did were educated specifically for that treatment.
    Background therapy
    		 Patient councelling and education, tailored self-care approaches aimed at jaw relaxation and tailored physiotherapy exercises for the jaw. Biofeedback training with EMG.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Aug 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 72
    Worldwide total number of subjects
    72
    EEA total number of subjects
    72
    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)
    71
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 72 patients were recruited between August 26th 2022 and April 30th 2023 for both study sites "Specialistkliniken för bettfysiologi Mölndal" and "Specialistkliniken för bettfysiologi Göteborg". 36 were randomized to treatment with Botulinumtoxin A and 36 to saline (placebo).

    Pre-assignment
    Screening details
    		 Patients were age ≥18 years, diagnosis of myalgia according to the DC/TMD (22), a minimum of six months of conservative treatment consisting of at least patient counselling, physiotherapy and biofeedback relaxation training, residual pain intensity related to orofacial myalgia of at least 40mm on 0–100 mm visual analogue scale (VAS) a

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 Botulinum toxin A (trade name Botox Allergan) powder for solution for injection. Using 1.0ml of sterile saline solution (Natriumklorid Fresenius Kabi 9mg/ml) the botulinumtoxin A was dissolved resulting in 100U/ml. Patients randomized to this treatment arm were injected with a total of 1ml (100U) in a total of 10 points. 2 points on each side of the temporalis muscle and 3 points to each side of the masseter muscle, using a monopolar EMG device.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Botox
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for solution for injection
    Routes of administration
    Injection
    Dosage and administration details
    Botox Allergan 100U was prepared by using 1.0ml of sterile saline solution (Natrium Fresenius Kabi 9mg/ml) to dissolve the botulinumtoxin A. 0.1ml then equalled 10U. A total of 10 points were injected with 10U per point, 2 on each side of the temporalis muscle and 3 to each side of the masseter muscle using a monopolar EMG device.

    Arm title
    		 Placebo
    Arm description
    		 Natriumklorid Fresenius Kabi 9mg/ml sterile saline solution was used as placebo. Patients randomized to this treatment arm were injected with a total of 1ml in a total of 10 points. 2 points on each side of the temporalis muscle and 3 points to each side of the masseter muscle, using a monopolar EMG device.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Natriumklorid Fresenius Kabi 9mg/ml
    Investigational medicinal product code
    Other name
    Saline
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    1ml Natriumklorid Fresenius Kabi 9mg/ml

    Number of subjects in period 1
    		Intervention Placebo
    Started
    36
    36
    Completed
    35
    34
    Not completed
    1
    2
         Pregnancy
    1
    -
         Lost to follow-up
    -
    1
         Protocol deviation
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 72 72
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 71 71
        From 65-84 years
    		 1 1
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 65 65
        Male
    		 7 7

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Botulinum toxin A (trade name Botox Allergan) powder for solution for injection. Using 1.0ml of sterile saline solution (Natriumklorid Fresenius Kabi 9mg/ml) the botulinumtoxin A was dissolved resulting in 100U/ml. Patients randomized to this treatment arm were injected with a total of 1ml (100U) in a total of 10 points. 2 points on each side of the temporalis muscle and 3 points to each side of the masseter muscle, using a monopolar EMG device.

    Reporting group title
    Placebo
    Reporting group description
    		 Natriumklorid Fresenius Kabi 9mg/ml sterile saline solution was used as placebo. Patients randomized to this treatment arm were injected with a total of 1ml in a total of 10 points. 2 points on each side of the temporalis muscle and 3 points to each side of the masseter muscle, using a monopolar EMG device.

    Primary: VAS pain reduction between baseline and 1 month

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    End point title
    		 VAS pain reduction between baseline and 1 month
    End point description
    End point type
    Primary
    End point timeframe
    1 month after first injection (baseline).
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    35
    36
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    15.4 ( 21.1 )
    14.5 ( 19.2 )
    Statistical analysis title
    		 t-test
    Statistical analysis description
    For comparison between groups t-test was used for continuous variables.
    Comparison groups
    Intervention v Placebo
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 t-test, 2-sided
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.645
         upper limit
    		 4.53
    Variability estimate
    Standard deviation

    Secondary: Change millimeter pain free mouth opening between baseline and 1month

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    End point title
    		 Change millimeter pain free mouth opening between baseline and 1month
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline and 1month after injection
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    35
    36
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    0.139 ( 7.407 )
    1.06 ( 9.95 )
    No statistical analyses for this end point

    Secondary: Evaluate if pain reduction is correlated to psychosocial factors at baseline

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    End point title
    		 Evaluate if pain reduction is correlated to psychosocial factors at baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Collected at baseline.
    End point values
    		 Intervention Placebo
    Number of subjects analysed
    36
    36
    Units: categories
    36
    36
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    August 26 2022 to January 18 2024
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    20241101
    Reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 Botulinum toxin A (trade name Botox Allergan) powder for solution for injection. Using 1.0ml of sterile saline solution (Natriumklorid Fresenius Kabi 9mg/ml) the botulinumtoxin A was dissolved resulting in 100U/ml. Patients randomized to this treatment arm were injected with a total of 1ml (100U) in a total of 10 points. 2 points on each side of the temporalis muscle and 3 points to each side of the masseter muscle, using a monopolar EMG device.

    Serious adverse events
    		 Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 36 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    27 / 36 (75.00%)
    Musculoskeletal and connective tissue disorders
    Jaw Pain
    Additional description: Increased jaw pain
         subjects affected / exposed
    10 / 36 (27.78%)
         occurrences all number
    10
    Headache
    Additional description: Increased headache
         subjects affected / exposed
    7 / 36 (19.44%)
         occurrences all number
    7
    Weakness of jaw muscles
    Additional description: Patient experience a weakening of their jaw muscles and difficulties chewing.
         subjects affected / exposed
    11 / 36 (30.56%)
         occurrences all number
    11
    Difficulty opening mouth
    Additional description: Patient experiences difficulty in opening their mouth.
         subjects affected / exposed
    4 / 36 (11.11%)
         occurrences all number
    4

    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
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    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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