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    Clinical Trial Results:
    Efficacy of DC071 mouthwash (0,2 % chlorhexidine digluconate) in peri-surgical care for preventing alveolar osteitis after third molar extraction. Prospective, multicenter, randomised, double-blind, placebo controlled study in parallel groups

    Summary
    EudraCT number
    2014-004682-24
    Trial protocol
    EE   LV   LT   FR   ES  
    Global end of trial date
    17 Feb 2016

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Nov 2018
    First version publication date
    30 Nov 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DC0071BB405
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Pierre Fabre Medicament
    Sponsor organisation address
    45 Place Abel Gance, Boulogne, France, 92100
    Public contact
    Centre de Recherche et Développement Pierre Fabre, Karim KEDDAD, MD, +33 (0)534506250, karim.keddad@pierre-fabre.com
    Scientific contact
    Centre de Recherche et Développement Pierre Fabre, Karim KEDDAD, MD, +33 (0)534506250, karim.keddad@pierre-fabre.com
    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
    02 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Feb 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Feb 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the efficacy of chlorhexidine mouthwash in the prevention of alveolar osteitis following third molar extraction.
    Protection of trial subjects
    The study was conducted according to Good Clinical Practice (GCP) (CPMP/ICH/135/95), the principles stated in the Declaration of Helsinki (1964) and its subsequent amendments thereto, and national regulations. The request for authorization by the Competent Authority or its notification (depending on National Régulations) was carried out by the Sponsor. The study protocol and related documents, including the informed consent forms (ICFs), were submitted for approval to independent, local or national Independent Ethics Committees (IECs) and to competent authorities (CAs) before the study set-up, according to national regulations.
    Background therapy
    In the context of management of post-surgical care, the following medications were to be systematically prescribed to limit post-operative oedema and pain: •Corticosteroids and level-2 analgesics (tramadol or paracetamol associated with codeine) were to be prescribed at a fixed dose during the first 48 hours post-surgery and progressively reduced over the subsequent 48 hours.
    Evidence for comparator
    Alveolar osteitis (AO), or dry socket, is one of the most common postoperative complications following the extraction or surgical removal of a tooth. It is defined as postoperative pain inside and around the extraction site, which increases in severity at any time between the first and third day after extraction, accompanied by a partial or total disintegrated blood clot within the alveolar socket, with or without halitosis. Antibacterial agents have been reported to reduce the incidence of AO and CHX digluconate is the most commonly used in dentistry and its efficacy has been widely validated. The use of a placebo was medically acceptable because all patients were followed by the investigator, informed that they may receive a placebo, and treated appropriately if needed
    Actual start date of recruitment
    30 Jan 2015
    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
    Estonia: 131
    Country: Number of subjects enrolled
    France: 72
    Country: Number of subjects enrolled
    Latvia: 103
    Country: Number of subjects enrolled
    Lithuania: 103
    Worldwide total number of subjects
    409
    EEA total number of subjects
    409
    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)
    409
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 414 patients requiring an impacted mandibular third molar extraction were selected/enrolled, 413 of them randomised (206 patients in the DC071 group and 207 in the placebo group) and 409 were treated. 41 centres in 4 countries (France, Estonia, Lithuania and Latvia) were initiated, of which, 33 were active (selected at least 1 patient).

    Pre-assignment
    Screening details
    A total of 417 patients were screened for study participation and signed an ICF. Of these, 3 patients were not enrolled (could not commit to the study agenda, consent withdrawal) and 1 patient was enrolled but not randomised. Women were included in the last week of their menstrual cycle in order to perform surgery with lower oestrogen level.

    Period 1
    Period 1 title
    Treatment period (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
    A randomisation list was established by the Clinical Pharmacy Department of the IRPF. This list was computer-generated with validated internal software. The randomisation methodology was validated by the Biometry Department of IRPF before generation. DC071 and placebo were formulated in mouthwash solutions identical in presentation (same size, same colour).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    DC071
    Arm description
    206 patients were randomised in the DC071 arm for seven days (Day -1 to Day 6). Of the 206 randomised patients, 203 of them received at least one dose treatment and 188 patients completed the treatment phase.
    Arm type
    Experimental

    Investigational medicinal product name
    DC071
    Investigational medicinal product code
    Other name
    Chlorhexidine digluconate 0.2%
    Pharmaceutical forms
    Mouthwash
    Routes of administration
    Buccal use
    Dosage and administration details
    The DC071 mouthwashes (0.2% CHX digluconate) were ready for use and were to be used pure and undiluted. The teeth were to be brushed prior to each use and the mouth then rinsed thoroughly with water before using the mouthwash. Patients rinsed with 10 mL for 1 min twice daily (in the morning and evening) for 7 days (Day -1 to Day 6). Patients began taking the mouthwash treatment the day prior (Day -1) to surgical extraction of the mandibular third molar (Visit 3, Day 1). On the day of the surgery (Day 1), the mouthwash treatment was performed in the morning just before the start of surgery (at the investigational centre) and in the evening (with a passive rinsing).

    Arm title
    Placebo
    Arm description
    207 patients were randomised in the Placebo arm for seven days (Day -1 to Day 6). Of the 207 randomised patients, 206 of them received at least one dose treatment and 185 patients completed the treatment phase.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Mouthwash
    Routes of administration
    Buccal use
    Dosage and administration details
    The placebo mouthwashes were ready for use and were to be used pure and undiluted. The teeth were to be brushed prior to each use and the mouth then rinsed thoroughly with water before using the mouthwash. Patients rinsed with 10 mL for 1 min twice daily (in the morning and evening) for 7 days (Day -1 to Day 6). Patients began taking the mouthwash treatment the day prior (Day -1) to surgical extraction of the mandibular third molar (Visit 3, Day 1). On the day of the surgery (Day 1), the mouthwash treatment was performed in the morning just before the start of surgery (at the investigational centre) and in the evening (with a passive rinsing).

    Number of subjects in period 1
    DC071 Placebo
    Started
    203
    206
    Completed
    188
    185
    Not completed
    15
    21
         Lack of efficacy
    12
    16
         Adverse event, non-fatal
    -
    3
         Personal reason
    1
    1
         Consent withdrawn by subject
    -
    1
         Lost to follow-up
    2
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    DC071
    Reporting group description
    206 patients were randomised in the DC071 arm for seven days (Day -1 to Day 6). Of the 206 randomised patients, 203 of them received at least one dose treatment and 188 patients completed the treatment phase.

    Reporting group title
    Placebo
    Reporting group description
    207 patients were randomised in the Placebo arm for seven days (Day -1 to Day 6). Of the 207 randomised patients, 206 of them received at least one dose treatment and 185 patients completed the treatment phase.

    Reporting group values
    DC071 Placebo Total
    Number of subjects
    203 206 409
    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)
    203 206 409
        From 65-84 years
    0 0 0
        85 years and over
    0 0 0
    Age continuous
    Age at first study drug intake
    Units: years
        median (inter-quartile range (Q1-Q3))
    26 (22 to 31) 26 (22 to 30) -
    Gender categorical
    Units: Subjects
        Female
    120 87 207
        Male
    83 119 202
    Regular smoker
    Units: Subjects
        Yes
    37 43 80
        No
    166 163 329
    Number of cigarettes per day
    Units: number
        median (inter-quartile range (Q1-Q3))
    5 (4 to 10) 7 (5 to 10) -

    End points

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    End points reporting groups
    Reporting group title
    DC071
    Reporting group description
    206 patients were randomised in the DC071 arm for seven days (Day -1 to Day 6). Of the 206 randomised patients, 203 of them received at least one dose treatment and 188 patients completed the treatment phase.

    Reporting group title
    Placebo
    Reporting group description
    207 patients were randomised in the Placebo arm for seven days (Day -1 to Day 6). Of the 207 randomised patients, 206 of them received at least one dose treatment and 185 patients completed the treatment phase.

    Primary: Absence of an alveolar osteitis

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    End point title
    Absence of an alveolar osteitis
    End point description
    The primary efficacy criterion was binary (success/failure) and was evaluated based on the absence/presence of an AO (alveolitis sicca, dry socket) within 7 days after the extraction of the third molar. A treatment failure was defined as the occurrence of an AO within 7 days after the extraction of the third molar.
    End point type
    Primary
    End point timeframe
    The presence of Alveolar osteitis was recorded within 7 days following extraction of the third mandibular molar.
    End point values
    DC071 Placebo
    Number of subjects analysed
    200
    205
    Units: not applicable
    number (not applicable)
        Success
    174
    165
        Failure
    26
    40
    Statistical analysis title
    Primary analysis
    Statistical analysis description
    The objective was to test the equality of the proportion between DC071 and placebo (primary hypothesis [H0]: pDC071 = pplacebo against the alternative H1: pDC071 ≠ pplacebo). The number of patients in failure was compared between DC071 and placebo, on the FAS, using a logistic regression adjusted for treatment, centre and smoker (Yes/No) and with the method of Firth’s penalised likelihood. The Odds Ratio (OR) and the corresponding 95% Wald CI were provided as a measure of the treatment effect.
    Comparison groups
    DC071 v Placebo
    Number of subjects included in analysis
    405
    Analysis specification
    Pre-specified
    Analysis type
    equivalence
    P-value
    = 0.074
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -
         upper limit
    -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were reported from the enrollment of patients to the end of study visit (Day 8 or Day 9 exceptionally)
    Adverse event reporting additional description
    At each visit, the occurrence of AEs since the last visit was determined by the patient’s spontaneous reporting, the investigator’s non-leading questioning and his/her clinical evaluation. The occurrence of Alveolar Osteitis and any related signs (pain, halitosis, swelling, etc.) were not reported as AEs.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    DC071
    Reporting group description
    -

    Reporting group title
    Placebo
    Reporting group description
    -

    Serious adverse events
    DC071 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 203 (0.00%)
    2 / 206 (0.97%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Abscess jaw
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    DC071 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    31 / 203 (15.27%)
    33 / 206 (16.02%)
    Injury, poisoning and procedural complications
    Postoperative wound complication
         subjects affected / exposed
    10 / 203 (4.93%)
    12 / 206 (5.83%)
         occurrences all number
    10
    12
    Post procedural swelling
         subjects affected / exposed
    8 / 203 (3.94%)
    9 / 206 (4.37%)
         occurrences all number
    8
    9
    Post procedural oedema
         subjects affected / exposed
    7 / 203 (3.45%)
    6 / 206 (2.91%)
         occurrences all number
    7
    6
    Procedural pain
         subjects affected / exposed
    7 / 203 (3.45%)
    9 / 206 (4.37%)
         occurrences all number
    7
    9
    Overdose
         subjects affected / exposed
    2 / 203 (0.99%)
    0 / 206 (0.00%)
         occurrences all number
    2
    0
    Post procedural complication
         subjects affected / exposed
    2 / 203 (0.99%)
    2 / 206 (0.97%)
         occurrences all number
    2
    2
    Procedural haemorrhage
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Social circumstances
    Poor personal hygiene
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Nervous system disorders
    Dysgeusia
         subjects affected / exposed
    3 / 203 (1.48%)
    0 / 206 (0.00%)
         occurrences all number
    3
    0
    Syncope
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    2 / 203 (0.99%)
    2 / 206 (0.97%)
         occurrences all number
    2
    2
    Gastrointestinal disorders
    Oral pruritus
         subjects affected / exposed
    3 / 203 (1.48%)
    0 / 206 (0.00%)
         occurrences all number
    3
    0
    Tongue discolouration
         subjects affected / exposed
    3 / 203 (1.48%)
    0 / 206 (0.00%)
         occurrences all number
    3
    0
    Tooth discolouration
         subjects affected / exposed
    2 / 203 (0.99%)
    0 / 206 (0.00%)
         occurrences all number
    2
    0
    Gingival erythema
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 206 (0.00%)
         occurrences all number
    1
    0
    Glossitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 206 (0.00%)
         occurrences all number
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 206 (0.00%)
         occurrences all number
    1
    0
    Endocrine disorders
    Hyperthyroidism
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Infections and infestations
    Post procedural cellulitis
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 206 (0.00%)
         occurrences all number
    1
    0
    Post procedural infection
         subjects affected / exposed
    1 / 203 (0.49%)
    0 / 206 (0.00%)
         occurrences all number
    1
    0
    Abscess jaw
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Abscess oral
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Alveolar osteitis
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1
    Tooth abscess
         subjects affected / exposed
    0 / 203 (0.00%)
    1 / 206 (0.49%)
         occurrences all number
    0
    1

    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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    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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