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    Clinical Trial Results:
    A pilot, double-blind, randomized, placebo-controlled, dose finding, proof of concept study to evaluate efficacy, safety and tolerability of self- administered subcutaneous diclofenac sodium 25-50-75mg/1ml in the treatment of an acute migraine attack with headache.

    Summary
    EudraCT number
    		 2017-004828-29
    Trial protocol
    		 IT  
    Global end of trial date
    22 Nov 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    20 Apr 2022
    First version publication date
    20 Apr 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    17I-DCsc09
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    IBSA, Institut Biochimique S.A
    Sponsor organisation address
    Via del Piano, Pambio-Noranco, Switzerland, 6915
    Public contact
    Servizio Informazione sulla Sperime, Pharmaceutical Development and Services srl, 0041 583601000, rd@ibsa.ch
    Scientific contact
    Servizio Informazione sulla Sperime, Pharmaceutical Development and Services srl, 0039 0557224179, rd@ibsa.ch
    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
    03 Apr 2020
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Nov 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of diclofenac sodium administered subcutaneously at three different doses (25-50-75 mg/1ml) in comparison to placebo in the treatment of an acute migraine attack with headache.
    Protection of trial subjects
    Adult out-patients with a diagnosis of migraine, with or without aura. The treatment was self-administered at home at the occurrence of the migraine attack. Patients were allowed to take as a rescue medication (2 hours after the injection of the IMP/placebo) their usual attack medicine or drugs taken for the migraine-associated symptoms (i.e., nausea and vomit).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    30 Jun 2018
    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
    Italy: 122
    Worldwide total number of subjects
    122
    EEA total number of subjects
    122
    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)
    121
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Study conducted in 9 investigational study sites in Italy. First patient enrolled: 20 September 2018; Last patient completed: 22 November 2019

    Pre-assignment
    Screening details
    		 21 days max of screening period. A total of 139 patients were screened and 129 attended Visit 1 (baseline/randomization visit), while 9 patients were screening failures and 1 voluntary withdrew from the study. A total of 128 patients were randomised to the assigned treatment group (one more patient was a screening failure).

    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, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The Placebo solution was indistinguishable from the IMPs. It was contained in a prefilled syringe identical to the IMPs prefilled syringes

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Diclofenac 25 mg/ml
    Arm description
    		 1 ml single subcutaneous injection of diclofenac sodium 25 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diclofenac sodium 25mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection self-administered at home by the patients at the occurrence of the migraine attack

    Arm title
    		 Diclofenac 50 mg/ml
    Arm description
    		 1 ml single subcutaneous injection of diclofenac sodium 50 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diclofenac sodium 50 mg/ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection self-administered at home by the patients at the occurrence of the migraine attack

    Arm title
    		 Diclofenac 75 mg/ml
    Arm description
    		 1 ml single subcutaneous injection of diclofenac sodium 75 mg
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diclofenac sodium
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection self-administered at home by the patients at the occurrence of the migraine attack

    Arm title
    		 Placebo
    Arm description
    		 1 ml single subcutaneous injection of NaCl 0,9%
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Subcutaneous use
    Dosage and administration details
    SC injection self-administered at home by the patients at the occurrence of the migraine attack. Placebo indistinguishable from IMPs

    Number of subjects in period 1
    		Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Started
    31
    30
    30
    31
    Completed
    31
    30
    30
    31

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Diclofenac 25 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 25 mg

    Reporting group title
    Diclofenac 50 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 50 mg

    Reporting group title
    Diclofenac 75 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 75 mg

    Reporting group title
    Placebo
    Reporting group description
    		 1 ml single subcutaneous injection of NaCl 0,9%

    Reporting group values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo Total
    Number of subjects
    		 31 30 30 31 122
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 31 30 30 30 121
        From 65-84 years
    		 0 0 0 1 1
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 40.10 ± 11.36 38.80 ± 12.93 41.93 ± 10.43 43.26 ± 10.72 -
    Gender categorical
    Units: Subjects
        Female
    		 26 24 28 26 104
        Male
    		 5 6 2 5 18

    End points

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    End points reporting groups
    Reporting group title
    Diclofenac 25 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 25 mg

    Reporting group title
    Diclofenac 50 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 50 mg

    Reporting group title
    Diclofenac 75 mg/ml
    Reporting group description
    		 1 ml single subcutaneous injection of diclofenac sodium 75 mg

    Reporting group title
    Placebo
    Reporting group description
    		 1 ml single subcutaneous injection of NaCl 0,9%

    Primary: percentage of patients pain-free at 2 hours after the study drug injection

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    End point title
    		 percentage of patients pain-free at 2 hours after the study drug injection
    End point description
    number and percentage of patients pain-free at 2 hours after the study drug injection in the ITT population.
    End point type
    Primary
    End point timeframe
    Baseline-2 hours post treatment
    End point values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Number of subjects analysed
    31
    30
    30
    31
    Units: % of patients
    9
    14
    10
    5
    Statistical analysis title
    		 primary efficacy endpoint
    Statistical analysis description
    number and percentage of patients pain-free at 2 hours after the study drug injection in the ITT population
    Comparison groups
    Diclofenac 25 mg/ml v Diclofenac 50 mg/ml v Diclofenac 75 mg/ml v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - The primary efficacy endpoint, defined as proportion of subjects completely pain free (pain score= zero) at 2 hours after the study drug injection, will be compared between treatment groups (active groups versus placebo) by means of Chi-Square Test.
    [2] - Diclofenac 25mg/ml vs. placebo p= 0.2244 D50 vs. placebo p= 0.0100 D75 vs. placebo p= 0.1188

    Secondary: Percentage of patients with the absence of photophobia at 2 hours after the injection

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    End point title
    		 Percentage of patients with the absence of photophobia at 2 hours after the injection
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline-2 hours after the injection
    End point values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Number of subjects analysed
    31
    30
    30
    31
    Units: % of patients
    61
    80
    73
    52
    Statistical analysis title
    		 absence of photophobia at 2 hours after the injec
    Statistical analysis description
    Percentage of subjects with the absence of photophobia at 2 hours after the injection using a binary scale (present or absent) will be compared between treatment groups (active groups versus placebo) using Chi-Square Test;
    Comparison groups
    Diclofenac 25 mg/ml v Diclofenac 50 mg/ml v Diclofenac 75 mg/ml v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05 [3]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [3] - Diclofenac 25mg/ml vs. placebo p= 0.4422 Diclofenac 50mg/ml vs. placebo 0.0197 Diclofenac 75mg/ml vs. placebo 0.0801

    Secondary: Percentage of patients with the absence of phonophobia at 2 hours after the injection

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    End point title
    		 Percentage of patients with the absence of phonophobia at 2 hours after the injection
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline-2 hours after the treatment
    End point values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Number of subjects analysed
    31
    30
    30
    31
    Units: % of patients
    74
    80
    70
    71
    Statistical analysis title
    		 absence of phonophobia at 2 hours after the injec
    Statistical analysis description
    Percentage of subjects with the absence of phonophobia at 2 hours after the injection using a binary scale (present or absent) will be compared between treatment groups (active groups versus placebo) using Chi-Square Test;
    Comparison groups
    Diclofenac 25 mg/ml v Diclofenac 50 mg/ml v Diclofenac 75 mg/ml v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.005 [4]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [4] - Diclofenac 25mg/ml vs. placebo 0.7759 Diclofenac 50mg/ml vs. placebo 0.4128 Diclofenac 75mg/ml vs. placebo 0.9340

    Secondary: Percentage of patients with the absence of nausea at 2 hours after the injection

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    End point title
    		 Percentage of patients with the absence of nausea at 2 hours after the injection
    End point description
    End point type
    Secondary
    End point timeframe
    BAseline-2 hours after the treatment
    End point values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Number of subjects analysed
    31
    30
    30
    31
    Units: % of patients
    58
    87
    77
    61
    Statistical analysis title
    		 absence of nausea at 2 hours after the injection
    Statistical analysis description
    Percentage of subjects with absence of nausea at 2 hours after the injection using a binary scale (present or absent) will be compared between treatment groups (active groups versus placebo) using Chi-Square Test;
    Comparison groups
    Diclofenac 25 mg/ml v Diclofenac 50 mg/ml v Diclofenac 75 mg/ml v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.005 [5]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [5] - Diclofenac 25mg/ml vs. placebo 0.7957 Diclofenac 50mg/ml vs. placebo 0.0243 Diclofenac 75mg/ml vs. placebo 0.1948

    Secondary: Percentage of patients with the absence of vomit at 2 hours after the injection

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    End point title
    		 Percentage of patients with the absence of vomit at 2 hours after the injection
    End point description
    End point type
    Secondary
    End point timeframe
    Baseline-2 hours after the treatment
    End point values
    		 Diclofenac 25 mg/ml Diclofenac 50 mg/ml Diclofenac 75 mg/ml Placebo
    Number of subjects analysed
    31
    30
    30
    31
    Units: % of patients
    94
    97
    97
    100
    Statistical analysis title
    		 Absence of vomit at 2 hours after the injection
    Statistical analysis description
    Percentage of subjects with absence of vomit at 2 hours after the injection using a binary scale (present or absent) will be compared between treatment groups (active groups versus placebo) using Chi-Square Test
    Comparison groups
    Diclofenac 25 mg/ml v Diclofenac 50 mg/ml v Diclofenac 75 mg/ml v Placebo
    Number of subjects included in analysis
    122
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.005 [6]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [6] - Diclofenac 25mg/ml vs. placebo 0.1506 Diclofenac 50mg/ml vs. placebo 0.3054 Diclofenac 75mg/ml vs. placebo 0.3054

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    screening-End of study visit
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.0
    Reporting groups
    Reporting group title
    Diclofenac sodium 25mg
    Reporting group description
    		 -

    Reporting group title
    Diclofenac sodium 50mg
    Reporting group description
    		 -

    Reporting group title
    Diclofenac sodium 75mg
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Diclofenac sodium 25mg Diclofenac sodium 50mg Diclofenac sodium 75mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 31 (0.00%)
    0 / 30 (0.00%)
    0 / 30 (0.00%)
    0 / 31 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Diclofenac sodium 25mg Diclofenac sodium 50mg Diclofenac sodium 75mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    18 / 31 (58.06%)
    16 / 30 (53.33%)
    19 / 30 (63.33%)
    5 / 31 (16.13%)
    Nervous system disorders
    dizziness
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    3
    0
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    17 / 31 (54.84%)
    11 / 30 (36.67%)
    15 / 30 (50.00%)
    5 / 31 (16.13%)
         occurrences all number
    18
    13
    16
    6
    Injection site reaction
         subjects affected / exposed
    0 / 31 (0.00%)
    2 / 30 (6.67%)
    3 / 30 (10.00%)
    0 / 31 (0.00%)
         occurrences all number
    0
    2
    3
    0
    Injection site erithema
         subjects affected / exposed
    1 / 31 (3.23%)
    3 / 30 (10.00%)
    5 / 30 (16.67%)
    0 / 31 (0.00%)
         occurrences all number
    1
    3
    5
    0
    Injection site oedema
         subjects affected / exposed
    1 / 31 (3.23%)
    0 / 30 (0.00%)
    2 / 30 (6.67%)
    0 / 31 (0.00%)
         occurrences all number
    1
    0
    2
    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
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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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