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    Clinical Trial Results:
    Adjunctive antimicrobial therapy of periodontitis: Long-term effects on disease progression and oral microbiological colonization

    Summary
    EudraCT number
    2006-005854-61
    Trial protocol
    DE  
    Global end of trial date
    31 Dec 2011

    Results information
    Results version number
    v1(current)
    This version publication date
    05 Oct 2019
    First version publication date
    05 Oct 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    KKS/MueParo/Antibiotics and Periodo
    Additional study identifiers
    ISRCTN number
    ISRCTN64254080
    US NCT number
    NCT00707369
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    University Hospital Muenster
    Sponsor organisation address
    Domagkstr. 5, Muenster, Germany, 48149
    Public contact
    Prof. Dr. med. dent. Benjamin Ehmke University of Muenster Department of Periodontology, Prof. Dr. med. dent. Benjamin Ehmke University of Muenster Department of Periodontology, +49 251 8347059, ehmke@uni-muenster.de
    Scientific contact
    Prof. Dr. med. dent. Benjamin Ehmke University of Muenster Department of Periodontology, Prof. Dr. med. dent. Benjamin Ehmke University of Muenster Department of Periodontology , +49 251 8347059, ehmke@uni-muenster.de
    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
    25 May 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The addressed research objectives are: (i) What is the size of the benefit of an adjunctive empiric antibiotic therapy compared to standard mechanical debridement and oral hygiene instructions in a representative sample of German periodontitis patients? (ii) Does the administration of the antibiotic therapy delay recurrence of periodontitis in the general population and in specific high risk groups (e.g. smokers) under standard supportive therapy? (iii) Is the presence of specific microbial complexes a useful predictor of outcome and recurrence of periodontitis? (iv) Does the administration of the antibiotic therapy affect the oral health related quality of life?
    Protection of trial subjects
    In the proposed trial, control patients receive standard periodontal treatment and test patients standard therapy plus adjunctive antibiotics. In general, the side effects of these therapies are known and events causing early termination are extremely unlikely. However, an early termination strategy is foreseen in the proposed trial. Early termination (“exit strategy”) will depend on the incidence of “periodontal abscesses” as defined by Meng 1999, i.e., “localized purulent infection within the tissues adjacent to the periodontal pocket that may lead to destruction of periodontal ligament and alveolar bone”. Periodontal abscesses represent a dental emergency situation in periodontal therapy. Such abscesses are most frequently seen in patients receiving inadequate periodontal therapy or in untreated patients. Teeth showing periodontal abscesses can be maintained over years if they are treated adequately (McLeod et al. 1997). Therefore, this parameter helps discover inadequate therapy throughout the study without causing irreversible harm (i.e., tooth loss) to the participants. During interim analysis the incidence of periodontal abscesses in both groups will be calculated. In case of a 50% difference (at least 20% of all patients in one group must suffer from this condition) between the groups, the trial will be terminated immediately.
    Background therapy
    - Mechanical debridement -Supportive periodontal therapy in 3-month intervals
    Evidence for comparator
    Standard of care includes mechanical removal of the biofilm, i.e., initial subgingival debridement and lifelong supportive periodontal therapy. The outcome of mechanical therapy is variable and further disease progression may occur. Beyond this approach, patients might benefit from the adjunctive use of systemic antibiotics. Via saliva and serum, these agents may affect periodontal and intraoral sites inaccessible for mechanical therapy. Although systemic antibiotics are frequently used therapeutic agents in dentistry, their prescription often is not evidence-based (Palmer et al. 2000). In two recent systematic reviews of the impact of various adjunctive antibiotic agents in periodontal therapy released by the European Federation of Periodontology (EFP, Herrera et al. 2002) and the American Academy of Periodontology (AAP, Haffajee et al. 2003), methodological weaknesses of existing studies were described. Due to various study designs, small sample sizes, mixed populations, use of weak parameters for disease progression determination, and short duration of the studies, definitive conclusions about the efficacy of adjunctive antimicrobial therapy have not yet been possible. Both reviews concluded that adjunctive antimicrobial therapy may offer a clinical benefit but further studies are needed.
    Actual start date of recruitment
    01 Oct 2008
    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
    Germany: 506
    Worldwide total number of subjects
    506
    EEA total number of subjects
    506
    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)
    432
    From 65 to 84 years
    74
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    recruitment: October 2008-October 2009 Overall 3261 patients were screened, 1004 met the inclusion criteria, 461 declined to participate, and 506 were randomized.

    Pre-assignment
    Screening details
    All study centers (Departments of Periodontology of the Universities of Berlin (Humboldt), Dresden, Frankfurt, Gießen, Greifswald, Heidelberg, Münster (coordinating center), and Würzburg) have been selected with respect to their special expertise in the field of periodontology and their feasibility of adequate patient recruitment. During one year

    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, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    test group (antibiotics)
    Arm description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive an adjunctive antimicrobial therapy consisting of oral metronidazole 400mg and amoxicillin 500mg (three times daily, for seven days).
    Arm type
    Experimental

    Investigational medicinal product name
    Amoxicillin 3H2O 574 mg (Amoxicillin-ratiopharm 500mg®, Ratiopharm, Germany) and Metronidazole 400 mg (Flagyl® 400, Sanofi-Aventis, Germany)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Patients receive an adjunctive antimicrobial therapy consisting of oral metronidazole 400mg and amoxicillin 500mg (three times daily, for seven days)

    Arm title
    control group (placebo)
    Arm description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive two placebo drugs (three times daily, for seven days).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo P1 & P2 (Cellulosepowder, Lactose-Monohydrat, Magnesiumstearat (Ph. Eur.), mikrokristalline Cellulose)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Two placebo drugs, to be taken three times a day for seven days.

    Number of subjects in period 1
    test group (antibiotics) control group (placebo)
    Started
    251
    255
    Completed
    206
    200
    Not completed
    45
    55
         Protocol deviation
    42
    50
         Adverse event, serious fatal
    1
    1
         Adverse event, non-fatal
    2
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    test group (antibiotics)
    Reporting group description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive an adjunctive antimicrobial therapy consisting of oral metronidazole 400mg and amoxicillin 500mg (three times daily, for seven days).

    Reporting group title
    control group (placebo)
    Reporting group description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive two placebo drugs (three times daily, for seven days).

    Reporting group values
    test group (antibiotics) control group (placebo) Total
    Number of subjects
    251 255 506
    Age categorical
    Subjects included in the study aged from 18 to 75 years.
    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)
    212 220 432
        From 65-84 years
    39 35 74
        85 years and over
    0 0 0
    Age continuous
    Age in years at screening visit 1
    Units: years
        median (full range (min-max))
    51 (27 to 75) 49 (22 to 74) -
    Gender categorical
    female and male
    Units: Subjects
        Female
    122 124 246
        Male
    129 131 260
    Stratum
    Randomization was performed stratified by “extent of periodontal disease”, and “smoking habit”. Stratum 1 (non-/light smokers, < 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 2 (non-/light smokers, ≥ 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 3 (smoker, < 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 4 (smoker, ≥ 38% of teeth with pocket probing depth ≥ 6 mm)
    Units: Subjects
        Stratum 1
    167 169 336
        Stratum 2
    21 18 39
        Stratum 3
    51 51 102
        Stratum 4
    12 17 29
    Smoker
    Units: Subjects
        no
    166 174 340
        yes
    85 81 166
    Carbon monoxide status in the exhaled air
    Units: Subjects
        Missing
    1 3 4
        < 7 ppm
    186 187 373
        ≥ 7 ppm
    64 65 129
    Self-reported diabetes mellitus
    Units: Subjects
        no diabetes
    237 244 481
        diabetes
    14 11 25
    Carbon monoxide in the exhaled air
    Units: part per million
        median (inter-quartile range (Q1-Q3))
    1 (0 to 7) 1 (0 to 7) -
    Number of teeth
    Units: Frequency
        median (inter-quartile range (Q1-Q3))
    25 (22 to 27) 26 (23 to 28) -
    Mean pocket probing depth
    Units: mm
        median (inter-quartile range (Q1-Q3))
    3.38 (3.04 to 3.95) 3.33 (3.01 to 3.96) -
    Proportion of sites per patient with bleeding on probing (BOP)
    Units: percent
        median (inter-quartile range (Q1-Q3))
    34.0 (24.4 to 47.5) 32.1 (19.8 to 47.2) -
    Mean attachment level per patient
    Units: mm
        median (inter-quartile range (Q1-Q3))
    3.98 (3.39 to 4.63) 3.92 (3.42 to 4.73) -
    Mean gingival recession
    Units: mm
        median (inter-quartile range (Q1-Q3))
    0.41 (0.16 to 0.77) 0.44 (0.15 to 0.86) -
    Proportion of sites per patient with plaque
    Units: percent
        median (inter-quartile range (Q1-Q3))
    36.1 (20.0 to 53.1) 31.3 (16.1 to 53.5) -
    OHIP summary score
    Summary score of the Oral Health Impact Profile – German Version (OHIP-G 49) questionnaire
    Units: Points
        median (inter-quartile range (Q1-Q3))
    38.7 (19.5 to 65.2) 31.6 (17.4 to 58.0) -
    Subject analysis sets

    Subject analysis set title
    Test group (antibiotics, ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat collective (test group) contains all patients who were randomized to receive antibiotics and had measurents at the baseline visit and final visit (27.5 months) after randomization. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations. Within 1.5 months after baseline examination (visit 2), patients received supra- and subgingival debridement in up to two sessions on two consecutive days. All mechanical therapy was performed with different hand instruments and/or machine driven scalers. After completion of mechanical therapy, in the antibiotics group patients received two empiric antibiotics [amoxicillin 3H2O 574 mg (Amoxicillin-ratiopharm 500 mg®, Ratiopharm, Germany); metronidazole 400 mg (Flagyl® 400, Sanofi-Aventis, Germany)] each to be taken three times a day for seven days.

    Subject analysis set title
    Control group (placebo, ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat collective (test group) contains all patients who were randomized to receive placebo and had measurents at the baseline visit and final visit (27.5 months) after randomization. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations.. Within 1.5 months after baseline examination (visit 2), patients received supra- and subgingival debridement in up to two sessions on two consecutive days. All mechanical therapy was performed with different hand instruments and/or machine driven scalers. After completion of mechanical therapy, in the placebo group patients received two placebo drugs each to be taken three times a day for seven days.

    Subject analysis set title
    Test group (antibiotics, PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (test groups) includes all patients who were randomized to receive antibiotics, had measurements of the relative attachment level at all visits (2, 4, 6, 8, 10, 12), and took the assigned drugs 18 to 23 times over 6-8 days.

    Subject analysis set title
    Control group (placebo, PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (control groups) includes all patients who were randomized to receive placebo, had measurements of the relative attachment level at all visits (2, 4, 6, 8, 10, 12), and took the assigned drugs 18 to 23 times over 6-8 days.

    Subject analysis sets values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects
    206
    200
    170
    175
    Age categorical
    Subjects included in the study aged from 18 to 75 years.
    Units: Subjects
        In utero
    0
    0
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
    0
    0
        Newborns (0-27 days)
    0
    0
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
    0
    0
        Children (2-11 years)
    0
    0
    0
    0
        Adolescents (12-17 years)
    0
    0
    0
    0
        Adults (18-64 years)
    174
    169
    143
    145
        From 65-84 years
    32
    31
    27
    30
        85 years and over
    0
    0
    0
    0
    Age continuous
    Age in years at screening visit 1
    Units: years
        median (full range (min-max))
    52 (27 to 75)
    51 (22 to 74)
    52 (27 to 75)
    52 (22 to 74)
    Gender categorical
    female and male
    Units: Subjects
        Female
    104
    96
    85
    87
        Male
    102
    104
    85
    88
    Stratum
    Randomization was performed stratified by “extent of periodontal disease”, and “smoking habit”. Stratum 1 (non-/light smokers, < 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 2 (non-/light smokers, ≥ 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 3 (smoker, < 38% of teeth with pocket probing depth ≥ 6 mm) Stratum 4 (smoker, ≥ 38% of teeth with pocket probing depth ≥ 6 mm)
    Units: Subjects
        Stratum 1
    142
    141
    123
    130
        Stratum 2
    18
    15
    10
    12
        Stratum 3
    39
    33
    35
    26
        Stratum 4
    7
    11
    2
    7
    Smoker
    Units: Subjects
        no
    145
    147
    121
    131
        yes
    61
    53
    49
    44
    Carbon monoxide status in the exhaled air
    Units: Subjects
        Missing
    1
    3
    1
    3
        < 7 ppm
    159
    156
    132
    138
        ≥ 7 ppm
    46
    41
    37
    34
    Self-reported diabetes mellitus
    Units: Subjects
        no diabetes
    197
    190
    163
    165
        diabetes
    9
    10
    7
    10
    Carbon monoxide in the exhaled air
    Units: part per million
        median (inter-quartile range (Q1-Q3))
    1 (0 to 5)
    1 (0 to 3)
    1 (0 to 4)
    1 (0 to 3)
    Number of teeth
    Units: Frequency
        median (inter-quartile range (Q1-Q3))
    25 (22 to 28)
    26 (23 to 28)
    25 (22 to 27)
    26 (23 to 28)
    Mean pocket probing depth
    Units: mm
        median (inter-quartile range (Q1-Q3))
    3.35 (3.04 to 3.89)
    3.33 (2.97 to 3.96)
    3.34 (3.03 to 3.89)
    3.34 (2.97 to 3.96)
    Proportion of sites per patient with bleeding on probing (BOP)
    Units: percent
        median (inter-quartile range (Q1-Q3))
    33.3 (24.2 to 46.7)
    32.2 (20.6 to 47.2)
    34.1 (24.4 to 48.5)
    32.6 (21.4 to 47.1)
    Mean attachment level per patient
    Units: mm
        median (inter-quartile range (Q1-Q3))
    3.94 (3.41 to 4.55)
    3.89 (3.43 to 4.72)
    3.95 (3.37 to 4.56)
    3.89 (3.49 to 4.68)
    Mean gingival recession
    Units: mm
        median (inter-quartile range (Q1-Q3))
    0.41 (0.16 to 0.79)
    0.45 (0.16 to 0.87)
    0.42 (0.16 to 0.79)
    0.45 (0.15 to 0.83)
    Proportion of sites per patient with plaque
    Units: percent
        median (inter-quartile range (Q1-Q3))
    36.0 (20.4 to 54.2)
    31.0 (16.0 to 53.2)
    35.8 (18.6 to 53.1)
    30.0 (15.2 to 54.6)
    OHIP summary score
    Summary score of the Oral Health Impact Profile – German Version (OHIP-G 49) questionnaire
    Units: Points
        median (inter-quartile range (Q1-Q3))
    36.0 (19.0 to 59.0)
    30.0 (17.0 to 54.3)
    36.0 (20.0 to 61.8)
    29.3 (16.0 to 51.0)

    End points

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    End points reporting groups
    Reporting group title
    test group (antibiotics)
    Reporting group description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive an adjunctive antimicrobial therapy consisting of oral metronidazole 400mg and amoxicillin 500mg (three times daily, for seven days).

    Reporting group title
    control group (placebo)
    Reporting group description
    All patients receive routine supragingival and subgingival debridement with sonic/ultrasonic scalers using micro tips or hand instruments (curettes) under local anesthesia. Finally, polishing with an air powder device or pumice and rotating rubber cups is performed. Initial therapy is performed in two sessions on two consecutive days. After completion of mechanical debridement, patients receive two placebo drugs (three times daily, for seven days).

    Subject analysis set title
    Test group (antibiotics, ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat collective (test group) contains all patients who were randomized to receive antibiotics and had measurents at the baseline visit and final visit (27.5 months) after randomization. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations. Within 1.5 months after baseline examination (visit 2), patients received supra- and subgingival debridement in up to two sessions on two consecutive days. All mechanical therapy was performed with different hand instruments and/or machine driven scalers. After completion of mechanical therapy, in the antibiotics group patients received two empiric antibiotics [amoxicillin 3H2O 574 mg (Amoxicillin-ratiopharm 500 mg®, Ratiopharm, Germany); metronidazole 400 mg (Flagyl® 400, Sanofi-Aventis, Germany)] each to be taken three times a day for seven days.

    Subject analysis set title
    Control group (placebo, ITT)
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intention-to-treat collective (test group) contains all patients who were randomized to receive placebo and had measurents at the baseline visit and final visit (27.5 months) after randomization. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations. The patients will be analyzed using the intention-to-treat principle (ITT) according to the randomized treatment regardless of protocol violations.. Within 1.5 months after baseline examination (visit 2), patients received supra- and subgingival debridement in up to two sessions on two consecutive days. All mechanical therapy was performed with different hand instruments and/or machine driven scalers. After completion of mechanical therapy, in the placebo group patients received two placebo drugs each to be taken three times a day for seven days.

    Subject analysis set title
    Test group (antibiotics, PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (test groups) includes all patients who were randomized to receive antibiotics, had measurements of the relative attachment level at all visits (2, 4, 6, 8, 10, 12), and took the assigned drugs 18 to 23 times over 6-8 days.

    Subject analysis set title
    Control group (placebo, PP)
    Subject analysis set type
    Per protocol
    Subject analysis set description
    The per-protocol population (control groups) includes all patients who were randomized to receive placebo, had measurements of the relative attachment level at all visits (2, 4, 6, 8, 10, 12), and took the assigned drugs 18 to 23 times over 6-8 days.

    Primary: Proportion of sites per patient with new clinical attachment loss (PSAL) ≥ 1.3 mm between baseline and the 27.5 months visit

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    End point title
    Proportion of sites per patient with new clinical attachment loss (PSAL) ≥ 1.3 mm between baseline and the 27.5 months visit
    End point description
    End point type
    Primary
    End point timeframe
    PSAL was determined for each patient by calculating the percentage of sites with a larger deterioration than 1.3 mm in the relative attachment level (mm) between baseline (visit 2) and 27.5 months (visit 12).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    206
    200
    170
    175
    Units: percent
        median (inter-quartile range (Q1-Q3))
    5.3 (3.1 to 9.9)
    7.8 (4.7 to 14.1)
    5.3 (3.2 to 9.7)
    7.5 (4.5 to 14.4)
    Statistical analysis title
    Primary efficacy analysis PSAL (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The confirmatory analysis of the primary endpoint was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    406
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    < 0.001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Notes
    [1] - A two-sided p-value less than 0.05 will be considered as significant.
    Statistical analysis title
    Sensitivity analysis PSAL (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    < 0.001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Proportion of sites per patient with new clinical attachment gain (PSAG) ≥ 1.3 mm between baseline and the 27.5 months visit

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    End point title
    Proportion of sites per patient with new clinical attachment gain (PSAG) ≥ 1.3 mm between baseline and the 27.5 months visit
    End point description
    End point type
    Secondary
    End point timeframe
    PSAG was determined for each patient by calculating the percentage of sites with a larger improvement than 1.3 mm in the relative attachment level (mm) between baseline (visit 2) and 27.5 months (visit 12).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    206
    200
    170
    175
    Units: percent
        median (inter-quartile range (Q1-Q3))
    19.4 (10.4 to 32.7)
    12.2 (7.1 to 23.0)
    19.6 (10.3 to 32.1)
    12.8 (7.2 to 23.5)
    Statistical analysis title
    Secondary analysis (PSAG >= 1.3 mm) ITT
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    406
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Secondary analysis (PSAG >= 1.3 mm) PP
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Proportion of sites per patient with new clinical attachment loss (PSAL) ≥ 1.3 mm between reevaluation (visit 4) and the 27.5 months visit

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    End point title
    Proportion of sites per patient with new clinical attachment loss (PSAL) ≥ 1.3 mm between reevaluation (visit 4) and the 27.5 months visit
    End point description
    End point type
    Secondary
    End point timeframe
    PSAL was determined for each patient by calculating the percentage of sites with a larger deterioration than 1.3 mm in the relative attachment level (mm) between reevalution (visit 4, after therapy) and 27.5 months (visit 12).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    206
    200
    170
    175
    Units: percent
        median (inter-quartile range (Q1-Q3))
    8.3 (4.7 to 13.5)
    10.6 (5.8 to 16.7)
    8.2 (4.5 to 13.2)
    10.7 (5.6 to 16.7)
    Statistical analysis title
    Secondary analysis PSAL from reevaluation (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    406
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0266
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Secondary analysis PSAL from reevaluation (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0124
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in proportion of sites per patient with bleeding on probing (BOP) between baseline and 27.5 months

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    End point title
    Change in proportion of sites per patient with bleeding on probing (BOP) between baseline and 27.5 months
    End point description
    End point type
    Secondary
    End point timeframe
    The change in the proportion of sites per patient with bleeding on probing (BOP) was calculated between 27.5 months and baseline (visit 12 minus visit 2).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    204
    200
    170
    175
    Units: percent
        median (inter-quartile range (Q1-Q3))
    -22.2 (-36.1 to -8.2)
    -12.1 (-27.7 to -2.7)
    -22.4 (-36.7 to -9.0)
    -12.3 (-28.4 to -3.0)
    Statistical analysis title
    Change BOP (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    404
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Change BOP (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in mean pocket probing depth (27.5 months - baseline)

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    End point title
    Change in mean pocket probing depth (27.5 months - baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    The absolute change in PPD was calculated between 27.5 months (visit 12) and baseline (visit 2).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    205
    200
    170
    175
    Units: mm
        median (inter-quartile range (Q1-Q3))
    -1.05 (-1.59 to -0.58)
    -0.80 (-1.28 to -0.42)
    -1.04 (-1.58 to -0.66)
    -0.82 (-1.29 to -0.43)
    Statistical analysis title
    Change PPD (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Control group (placebo, ITT) v Test group (antibiotics, ITT)
    Number of subjects included in analysis
    405
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Change PPD (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    < 0.0001
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in mean attachment level (27.5 months - baseline)

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    End point title
    Change in mean attachment level (27.5 months - baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in mean attachment level was calculated between 27.5 months (visit 12) and baseline (visit 2).
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    205
    200
    170
    175
    Units: mm
        median (inter-quartile range (Q1-Q3))
    -0.64 (-1.02 to -0.19)
    -0.38 (-0.86 to 0.05)
    -0.60 (-0.97 to -0.19)
    -0.39 (-1.09 to -0.30)
    Statistical analysis title
    Change attachment (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    405
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0004
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Change attachment (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    405
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0017
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in mean gingival recession (27.5 months - baseline)

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    End point title
    Change in mean gingival recession (27.5 months - baseline)
    End point description
    End point type
    Secondary
    End point timeframe
    Change in the mean gingival recession per patient was calculated between 27.5 months and baseline (visit 12 - visit 2)
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    205
    200
    170
    175
    Units: mm
        median (inter-quartile range (Q1-Q3))
    0.49 (0.22 to 0.90)
    0.51 (0.19 to 0.85)
    0.46 (0.19 to 0.80)
    0.40 (0.16 to 0.71)
    Statistical analysis title
    Change Recession (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    405
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.2186
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Change Recession (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per-protocol collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.1011
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in proportion of sites per patient with plaque between 27.5 months and baseline

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    End point title
    Change in proportion of sites per patient with plaque between 27.5 months and baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change of the proportion of sites per patient with detectable plaque was calculated between 27.5 months and baseline (visit12 - visit2)
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    205
    200
    170
    175
    Units: percent
        median (inter-quartile range (Q1-Q3))
    0.56 (-17.82 to 17.59)
    0.90 (-17.1 to 20.15)
    0.70 (-17.78 to 17.19)
    0.33 (-17.59 to 22.39)
    Statistical analysis title
    Change Plaque (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    405
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.9649
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval
    Statistical analysis title
    Change Plaque (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a stratified Wilcoxon-Test (van Elteren). The four strata were defined as follows: stratum 1 (localized periodontal disease, non-/light smoker), stratum 2 (generalized periodontal disease, non-/light smoker), stratum 3 (localized periodontal disease, smoker) and stratum 4 (generalized periodontal disease, smoker).
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    345
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.8658
    Method
    Stratified Wilcoxon test (van Elteren)
    Confidence interval

    Secondary: Change in OHIP summary score between 27.5 months and baseline

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    End point title
    Change in OHIP summary score between 27.5 months and baseline
    End point description
    End point type
    Secondary
    End point timeframe
    Change in the summary score of the Oral Health Impact Profile – German Version (OHIP-G 49) questionnaire between 27.5 months (visit 12) and baseline (visit 2)
    End point values
    Test group (antibiotics, ITT) Control group (placebo, ITT) Test group (antibiotics, PP) Control group (placebo, PP)
    Number of subjects analysed
    200
    195
    164
    170
    Units: Points
        median (inter-quartile range (Q1-Q3))
    -7.8 (-26.2 to -3.4)
    -4.3 (-17.0 to 5.4)
    -7.0 (-25.7 to 4.0)
    -3.6 (-16.0 to 6.0)
    Statistical analysis title
    Change OHIP score (27.5 months - baseline) (ITT)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the intention-to-treat collective. The analysis was performed using a two-sided Mann-Whitney U test.
    Comparison groups
    Test group (antibiotics, ITT) v Control group (placebo, ITT)
    Number of subjects included in analysis
    395
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0432
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    Change OHIP score (27.5 months - baseline) (PP)
    Statistical analysis description
    Comparison between the antibiotics and placebo group in the per protocol collective. The analysis was performed using a two-sided Mann-Whitney U test.
    Comparison groups
    Test group (antibiotics, PP) v Control group (placebo, PP)
    Number of subjects included in analysis
    334
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.0731
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    01.10.2008 - 31.12.2011
    Adverse event reporting additional description
    All adverse events occurring during the trial period including the 14 days after visit 12 (informed consent – visit 12) have to be documented in the AE-form of the CRF including assessment of severity.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    14.1
    Reporting groups
    Reporting group title
    Test group (antibiotics)
    Reporting group description
    -

    Reporting group title
    control group (placebo)
    Reporting group description
    -

    Serious adverse events
    Test group (antibiotics) control group (placebo)
    Total subjects affected by serious adverse events
         subjects affected / exposed
    38 / 251 (15.14%)
    29 / 255 (11.37%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    1
    1
    Surgical and medical procedures
    Adenoidectomy
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Caecum operation
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hernia repair
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hysterectomy
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nasal septal operation
         subjects affected / exposed
    2 / 251 (0.80%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Polypectomy
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sinus operation
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Stent placement
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Thoracic operation
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cervix carcinoma
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatic cancer metastatic
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laryngeal cancer
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Prostate cancer
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Immune system disorders
    Anaphylactic reaction
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Unevaluable event
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    1 / 1
    Psychiatric disorders
    Burnout syndrome
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Completed suicide
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    1 / 1
    0 / 0
    Reproductive system and breast disorders
    Adenomyosis
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Clavicle fracture
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Fall
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Head injury
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint dislocation
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint injury
         subjects affected / exposed
    0 / 251 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ligament injury
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Road traffic accident
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    2 / 251 (0.80%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Upper limb fracture
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Investigations
    Inflammatory marker increased
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Angina pectoris
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arrhythmia
         subjects affected / exposed
    1 / 251 (0.40%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Atrial flutter
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac discomfort
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Coronary artery stenosis
         subjects affected / exposed
    1 / 251 (0.40%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myocardial infarction
         subjects affected / exposed
    2 / 251 (0.80%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Laryngeal inflammation
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord cyst
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord inflammation
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vocal cord leukoplakia
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Cerebrovascular accident
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dementia
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Headache
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Myasthenia gravis
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Transient ischaemic attack
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eye disorders
    Macular fibrosis
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Retinal detachment
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    VIIIth nerve lesion
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    0 / 251 (0.00%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Haemorrhoids
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ileus
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Inguinal hernia
         subjects affected / exposed
    2 / 251 (0.80%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intestinal haemorrhage
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Umbilical hernia
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Vomiting
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Renal and urinary disorders
    Pelvi-ureteric obstruction
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Arthritis reactive
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Back pain
         subjects affected / exposed
    1 / 251 (0.40%)
    2 / 255 (0.78%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cervical spinal stenosis
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    2 / 251 (0.80%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Joint swelling
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal discomfort
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Osteoarthritis
         subjects affected / exposed
    2 / 251 (0.80%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rheumatoid arthritis
         subjects affected / exposed
    2 / 251 (0.80%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Rotator cuff syndrome
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Scleroderma
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tibia fracture
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Appendicitis
         subjects affected / exposed
    1 / 251 (0.40%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Bacteraemia
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Device related infection
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Orchitis
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 251 (0.40%)
    0 / 255 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Sepsis
         subjects affected / exposed
    0 / 251 (0.00%)
    1 / 255 (0.39%)
         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: 5%
    Non-serious adverse events
    Test group (antibiotics) control group (placebo)
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    178 / 251 (70.92%)
    177 / 255 (69.41%)
    Vascular disorders
    Hypertension
         subjects affected / exposed
    5 / 251 (1.99%)
    8 / 255 (3.14%)
         occurrences all number
    5
    8
    Injury, poisoning and procedural complications
    Tooth fracture
         subjects affected / exposed
    9 / 251 (3.59%)
    16 / 255 (6.27%)
         occurrences all number
    9
    19
    Surgical and medical procedures
    Artificial crown procedure
         subjects affected / exposed
    6 / 251 (2.39%)
    13 / 255 (5.10%)
         occurrences all number
    8
    13
    Dental prosthesis placement
         subjects affected / exposed
    7 / 251 (2.79%)
    7 / 255 (2.75%)
         occurrences all number
    7
    7
    Endodontic procedure
         subjects affected / exposed
    4 / 251 (1.59%)
    12 / 255 (4.71%)
         occurrences all number
    4
    15
    Tooth extraction
         subjects affected / exposed
    26 / 251 (10.36%)
    20 / 255 (7.84%)
         occurrences all number
    28
    21
    Tooth repair
         subjects affected / exposed
    7 / 251 (2.79%)
    10 / 255 (3.92%)
         occurrences all number
    9
    14
    General disorders and administration site conditions
    Device failure
         subjects affected / exposed
    28 / 251 (11.16%)
    28 / 255 (10.98%)
         occurrences all number
    41
    31
    Influenza like illness
         subjects affected / exposed
    9 / 251 (3.59%)
    14 / 255 (5.49%)
         occurrences all number
    9
    15
    Gastrointestinal disorders
    Dental caries
         subjects affected / exposed
    34 / 251 (13.55%)
    33 / 255 (12.94%)
         occurrences all number
    40
    36
    Dental pulp disorder
         subjects affected / exposed
    22 / 251 (8.76%)
    12 / 255 (4.71%)
         occurrences all number
    25
    12
    Periodontitis
         subjects affected / exposed
    7 / 251 (2.79%)
    14 / 255 (5.49%)
         occurrences all number
    9
    17
    Tooth disorder
         subjects affected / exposed
    17 / 251 (6.77%)
    17 / 255 (6.67%)
         occurrences all number
    21
    23
    Toothache
         subjects affected / exposed
    6 / 251 (2.39%)
    13 / 255 (5.10%)
         occurrences all number
    7
    16
    Diarrhoea
         subjects affected / exposed
    11 / 251 (4.38%)
    2 / 255 (0.78%)
         occurrences all number
    13
    1
    Infections and infestations
    Influenza
         subjects affected / exposed
    7 / 251 (2.79%)
    6 / 255 (2.35%)
         occurrences all number
    9
    7
    Nasopharyngitis
         subjects affected / exposed
    18 / 251 (7.17%)
    14 / 255 (5.49%)
         occurrences all number
    21
    14
    Tooth abscess
         subjects affected / exposed
    6 / 251 (2.39%)
    23 / 255 (9.02%)
         occurrences all number
    6
    31

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    06 Dec 2007
    -During visit eight a blood sample will be given on a DNA storage card (e.g. FTA Elute Microcard, Whatman). The cards can be stored at room temperature and will be shipped collectively to the coordinating center for further processing at the end of the study. -EDTA-blood (10ml, 1 sample) will be taken during visits 1, 8 and 12 to determine the course of inflammatory disease parameters (e.g. CRP, etc.) and HbA1c. The sample will be shipped immediately for further processing in special gusseted wallets (to ensure specimen containment) to the clinical chemistry laboratory of the University of Greifswald.
    24 Jun 2008
    - Changes made for: Subject Inclusion Criteria, Subject Exclusion Criteria and Subject Withdrawal Criteria -EDTA-blood (10ml, 1 sample) will be taken during visits 1, 8 and 12 to determine the course of inflammatory disease parameters (e.g. CRP, etc.) and HbA1c. -At every visit the examiner has to perform a routine inspection. First the medical health history (MHH) has to be checked. Changes have to be documented in the MHH and the CRF. Changes within the medication must be also documented in the MHH and additionally in the CRF if they belonging to the following six medication groups: 1. Antibiotics, 2. ASS for more than 4 weeks, 3. Medication for cardiovascular and/ or heart diseases, 4. Medication for thyroid diseases, 5. Medication for gastro-intestinal diseases, 6. Medication for asthma (allergic/ bronchial). The medication group should be marked with a cross in the CRF and the name and dosage should be documented. Following the clinical inspection will be done. The existence of periodontal abscesses has to be excluded. If there is a periodontal abscess, the tooth has to be documented in the CRF as well. Additionally, the examiner has to check the occlusal relief versus the intraoral photographs of visit 2 (occlusal inspection at visits 4, 6, 8, 10, 12). Changes have to be documented in the CRF. Finally, it has to be proved if there were any adverse or serious adverse events. If yes, it has to be specified on AE/ SAE form. - Change: OHIP-G was changed to OHIP-G49 -The HbA1c will be assessed centralized at the Institut für Klinische Chemie und Laboratoriumsmedizin (IKCL), University of Greifswald. HbA1c will be assessed in the blood samples which are taken at visit one, eight and twelve. - New definitions for: Adverse reaction (AR) and Serious adverse event or serious adverse reaction (SAE or SAR)

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30326764
    http://www.ncbi.nlm.nih.gov/pubmed/27393928
    http://www.ncbi.nlm.nih.gov/pubmed/30825384
    http://www.ncbi.nlm.nih.gov/pubmed/29668720
    http://www.ncbi.nlm.nih.gov/pubmed/26250060
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