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    Clinical Trial Results:
    Local treatment of craniomandibular myofascial pain with the 5-HT3 receptor antagonist granisetron. A randomized and double-blind study.

    Summary
    EudraCT number
    2005-006042-41
    Trial protocol
    SE  
    Global end of trial date
    31 Dec 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    01 May 2021
    First version publication date
    01 May 2021
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    NC3-project
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02230371
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    17177, Stockholm, Sweden,
    Public contact
    Department of Dental Medicine, Section for Orofacial Pain and Jaw Function, Karolinska Institutet, Karolinska Institutet, nikolaos.christidis@ki.se
    Scientific contact
    Department of Dental Medicine, Section for Orofacial Pain and Jaw Function, Karolinska Institutet, Karolinska Institutet, nikolaos.christidis@ki.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
    31 Dec 2014
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim for the research project is to investigate if local treatment with granisetron reduces pain in patients with chronic craniomandibular myalgia.
    Protection of trial subjects
    The study was approved by the regional ethical review board in Stockholm, Sweden (2006/192-31/4) and by the Medical Products Agency in Uppsala, Sweden (151:2006/7947). Adverse events were systematically collected during the study period.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 May 2006
    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
    Sweden: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    40
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Study was carried out at two centers, the specialist clinics for Orofacial Pain and Jaw Function, Department of Dental Medicine, Karolinska Institutet, Huddinge, Sweden and Clinical Oral Physiology at the Eastman Institute, Stockholm Public Dental Health (Folktandvården Stockholms län AB), Stockholm, Sweden, between May 2006 and December 2014.

    Pre-assignment
    Screening details
    437 patients were screened, 40 were eligible and included. Inclusion criteria: age ≥18y, diagnosis of myofascial pain, duration of TMD-pain ≥3 months, self-assessed average M-TMD pain intensity ≥ 30 mm on a 100-mm VAS during one week prior to examination, pain upon digital palpation of the masseter and/or the temporalis muscles.

    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
    Blinding implementation details
    The study substances have identical appearance, smell and viscosity so both the patients and examiners were blinded to group assignment. A research assistant assigned the patients to treatment substance in consecutive order according to the randomization list, prepared the syringes and marked them with patient number. A numbered randomization list with the substances in random order in blocks of four was kept hidden to the examiners during the entire study.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Granisetron
    Arm description
    Granisetron was used as active treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).
    Arm type
    Experimental

    Investigational medicinal product name
    Granisetron
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Granisetron (KYTRIL®; 1 mg/mL, Roche, Stockholm, Sweden) was slowly injected into a maximum of six muscle sites in each patient. The most painful tender-points to palpation of the masticatory muscles were chosen, maximum 3 per muscle. The injected volume into each tender-point was 0.5 mL. Thus the maximum dose of granisetron a patient could receive was 3 mg per treatment.

    Arm title
    Isotonic saline (placebo)
    Arm description
    Isotonic saline was used as control treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).
    Arm type
    Placebo

    Investigational medicinal product name
    Isotonic saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Isotonic saline (NaCl; 0.9 mg/mL, Fresenius Kabi, Uppsala, Sweden) was slowly injected into a maximum of six muscle sites in each patient. The most painful tender-points to palpation of the masticatory muscles were chosen, maximum 3 per muscle. The injected volume into each tender-point was 0.5 mL.

    Number of subjects in period 1
    Granisetron Isotonic saline (placebo)
    Started
    20
    20
    Completed
    20
    20

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Granisetron
    Reporting group description
    Granisetron was used as active treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).

    Reporting group title
    Isotonic saline (placebo)
    Reporting group description
    Isotonic saline was used as control treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).

    Reporting group values
    Granisetron Isotonic saline (placebo) Total
    Number of subjects
    20 20 40
    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)
    20 20 40
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    38.3 ± 15.1 39.1 ± 16.1 -
    Gender categorical
    Units: Subjects
        Female
    18 19 37
        Male
    2 1 3
    Physical functioning
    Distribution of physical functioning assessed with the Graded Chronic Pain Scale (GCPS).
    Units: Subjects
        GCPS Grade 0
    5 12 17
        GCPS Grade I
    4 1 5
        GCPS Grade II
    9 4 13
        GCPS Grade III
    0 1 1
        GCPS Grade IV
    1 1 2
        Missing value
    1 1 2
    Pain intensity
    Weekly pain intensity (VAS; 0–100 mm). Reported as median (IQR).
    Units: Score
        median (standard deviation)
    52 ± 29 57 ± 24 -
    Limitation in jaw function
    Limitation in jaw function assessed with the Jaw Disability Checklist (JDC). Reported as median (IQR).
    Units: Score (0-12)
        median (standard deviation)
    3 ± 5 2 ± 4 -
    MWO without pain
    Maximum voluntary mouth opening capacity (MVO) without pain.
    Units: mm
        arithmetic mean (standard deviation)
    41.1 ± 9.3 44.0 ± 10.9 -
    MWO with pain
    Maximum voluntary mouth opening capacity (MVO) with pain.
    Units: mm
        arithmetic mean (standard deviation)
    49.7 ± 7.5 52.8 ± 10.0 -

    End points

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    End points reporting groups
    Reporting group title
    Granisetron
    Reporting group description
    Granisetron was used as active treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).

    Reporting group title
    Isotonic saline (placebo)
    Reporting group description
    Isotonic saline was used as control treatment. The study comprised seven visits; V1) Screening for study participation and inclusion, V2-V4), Injection of study substances, and V5) Follow-ups at 1-month. Those patients in any group that still reported more than 30 % improvement at the 1-month visit follow-up were scheduled for follow-ups also after 2- (V6) and 6-months (V7).

    Primary: Pain intensity at 1, 2, 6 months

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    End point title
    Pain intensity at 1, 2, 6 months
    End point description
    Weekly pain intensity (VAS; 0–100 mm). Reported as median (IQR).
    End point type
    Primary
    End point timeframe
    1, 2 and 6 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Score
    median (standard deviation)
        1 month
    29 ± 41
    29 ± 40
        2 months
    32 ± 30
    36 ± 25
        6 months
    24 ± 35
    34 ± 31
    Statistical analysis title
    Difference Pain intensity 1 month
    Statistical analysis description
    Difference in pain intensity at 1 month between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Difference Pain intensity 2 months
    Statistical analysis description
    Difference in pain intensity at 2 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.009
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Difference Pain intensity 6 months
    Statistical analysis description
    Difference in pain intensity at 2 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.031
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Limitation in jaw function at 1, 2, 6 months

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    End point title
    Limitation in jaw function at 1, 2, 6 months
    End point description
    Limitation in jaw function assessed with the Jaw Disability Checklist (JDC). Reported as median (IQR).
    End point type
    Secondary
    End point timeframe
    1, 2 and 6 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Score
    median (standard deviation)
        1 month
    3 ± 5
    2 ± 4.5
        2 months
    3 ± 4
    2 ± 5.5
        6 months
    3 ± 5
    1 ± 3.5
    Statistical analysis title
    Difference Limitation in jaw function 1,2,6months
    Statistical analysis description
    Difference in limitation in jaw function at 1, 2 and 6 months between Granisetron and placebo.
    Comparison groups
    Isotonic saline (placebo) v Granisetron
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: MWO without pain at 1, 2, 6 months

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    End point title
    MWO without pain at 1, 2, 6 months
    End point description
    Maximum voluntary mouth opening capacity (MVO) without pain.
    End point type
    Secondary
    End point timeframe
    1, 2 and 6 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: mm
    arithmetic mean (standard deviation)
        1 month
    42.9 ± 9.3
    47.6 ± 9.4
        2 months
    43.3 ± 9.4
    46.9 ± 9.4
        6 months
    47.2 ± 10.8
    46.1 ± 6.2
    Statistical analysis title
    Difference MWO without pain 1, 2, 6 months
    Statistical analysis description
    Difference in MWO without pain at 1, 2 and 6 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: MWO with pain at 1, 2, 6 months

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    End point title
    MWO with pain at 1, 2, 6 months
    End point description
    Maximum voluntary mouth opening capacity (MVO) with pain.
    End point type
    Secondary
    End point timeframe
    1, 2 and 6 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Score (0-12)
    arithmetic mean (standard deviation)
        1 month
    47.9 ± 8.2
    52.8 ± 9.5
        2 months
    49.2 ± 7.5
    51.3 ± 9.8
        6 months
    49.3 ± 10.5
    50.4 ± 7.5
    Statistical analysis title
    Difference MWO with pain 1, 2, 6 months
    Statistical analysis description
    Difference in MWO with pain at 1, 2 and 6 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Physical functioning at 1 month

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    End point title
    Physical functioning at 1 month
    End point description
    Distribution of physical functioning assessed with the Graded Chronic Pain Scale (GCPS).
    End point type
    Secondary
    End point timeframe
    1 month after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Distribution
        Grade 0
    8
    11
        Grade I
    6
    1
        Grade II
    4
    2
        Grade III
    1
    3
        Grade IV
    1
    0
        Missing value
    0
    3
    Statistical analysis title
    Difference Physical functioning 1 month
    Statistical analysis description
    Difference in Physical functioning at 1 month between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Physical functioning at 2 months

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    End point title
    Physical functioning at 2 months
    End point description
    Distribution of physical functioning assessed with the Graded Chronic Pain Scale (GCPS).
    End point type
    Secondary
    End point timeframe
    2 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Distribution
        Grade 0
    7
    6
        Grade I
    1
    1
        Grade II
    3
    1
        Grade III
    3
    0
        Grade IV
    1
    0
        Missing value
    5
    12
    Statistical analysis title
    Difference Physical functioning 2 months
    Statistical analysis description
    Difference in Physical functioning at 2 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Physical functioning at 6 months

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    End point title
    Physical functioning at 6 months
    End point description
    Distribution of physical functioning assessed with the Graded Chronic Pain Scale (GCPS).
    End point type
    Secondary
    End point timeframe
    6 months after repeated tender-point injections with Granisetron (active substance) or Isotonic saline (placebo).
    End point values
    Granisetron Isotonic saline (placebo)
    Number of subjects analysed
    20
    20
    Units: Distribution
        Grade 0
    6
    2
        Grade I
    1
    2
        Grade II
    1
    1
        Grade III
    2
    0
        Grade IV
    0
    0
        Missing value
    10
    15
    Statistical analysis title
    Difference Physical functioning at 6 months
    Statistical analysis description
    Difference in Physical functioning at 6 months between Granisetron and placebo.
    Comparison groups
    Granisetron v Isotonic saline (placebo)
    Number of subjects included in analysis
    40
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    > 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The patients were asked to list any adverse events during the week following each injection.
    Adverse event reporting additional description
    If any adverse event occurred the patients were asked to describe the event and to grad it as mild, moderate or severe. Only mild and short-lasting adverse events were reported after the first injections and no specific dictionary or frequency threshold was used.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    No specific was used
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    Granisetron and control
    Reporting group description
    -

    Serious adverse events
    Granisetron and control
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 40 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Granisetron and control
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 40 (10.00%)
    Gastrointestinal disorders
    Nausea, constipation, dizziness, hematoma and itching
    Additional description: 4 patients in both groups reported mild, short lasting adverse events, such as nausea, constipation, dizziness, hematoma and itching after the first injection of substance. These adverse events did not occur after the second and third injections.
         subjects affected / exposed
    4 / 40 (10.00%)
         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.
    The results are robust but a limited number of patients participated. The generalizability of the findings should also be investigated in other chronic pain disorders both local and generalized, such as work-related trapezius myalgia or fibromyalgi.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/26634569
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