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    Clinical Trial Results:
    Surgical treatment of peri-implantitis with and without systemically adjunctive antibiotics A prospective, open, randomized, three armed, parallel, placebo controlled clinical trial

    Summary
    EudraCT number
    		 2013-004724-11
    Trial protocol
    		 SE  
    Global end of trial date
    27 May 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    13 Jul 2024
    First version publication date
    13 Jul 2024
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    294568
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Karolinska Institutet
    Sponsor organisation address
    Nobels väg 6, Solna, Sweden,
    Public contact
    Margareta Hultin, Karolinska Institute, +46 08524 882 48 , margareta.hultin@ki.se
    Scientific contact
    Margareta Hultin, Karolinska Institute, +46 08524 882 48 , margareta.hultin@ki.se
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    27 May 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    27 May 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    27 May 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the present study is to evaluate the adjunctive effect of systemically administered antibiotics during surgical treatment of peri-implantitis.
    Protection of trial subjects
    The study was approved by the Ethics Committee, Stockholm, Sweden (Dnr 2014-1331-31-1) and Swedish Medical Products Agency (EudraCT no 2013-004724-11) and conducted in accordance with the Helsinki Declaration as revised in 2013. CONSORT guidelines were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Apr 2015
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Efficacy, Scientific research
    Long term follow-up duration
    		 12 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Sweden: 84
    Worldwide total number of subjects
    84
    EEA total number of subjects
    84
    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)
    25
    From 65 to 84 years
    51
    85 years and over
    8

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were referred for peri-implantitis to the Department of Periodontology, Specialist Clinic Kaniken, Public Dental Health Service, Uppsala, Sweden and screened for eligibility prior to baseline examination. All patients were informed about the details of the study and asked to sign a consent before inclusion in the study.

    Pre-assignment
    Screening details
    		 Included patients were > 18 years with peri-implantitis, full-mouth plaque score (FMPS) of <= 30%, partially or completely edentulous with healthy or treated periodontal conditions enrolled in a regular supportive program.

    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
    		 Investigator, Data analyst, Subject

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Surgical treatment with amoxicillin + metronidazole
    Arm description
    		 Surgical treatment with amoxicillin 500mgx3x7 + metronidazole 400mgx3x7
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Amoxicillin Sandoz
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Amoxicillin Sandoz 500mgx3 for 7 days

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Flagyl Sanofi
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metronidazole Sanofi 400mgx3 for 7 days

    Arm title
    		 Surgical treatment with metronidazole + phenoxymethylpenicilli
    Arm description
    		 Surgical treatment with metronidazole 400mgx3x7 + phenoxymethylpenicillin (800mgx2), x3x7
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Flagyl Sanofi
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Metronidazole Sanofi 400mgx3 for 7 days

    Investigational medicinal product name
    PHENOXYMETHYLPENICILLIN
    Investigational medicinal product code
    Other name
    Kåvepenin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    800mgx2x3 for 7 days

    Arm title
    		 Surgical treatment with placebo amoxicillin + metronidazole
    Arm description
    		 Surgical treatment with placebo tablets amoxicillin 500mg and 400mg metronidazole, 2 capsules 3 times daily.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Amoxicillin placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Amoxicillin placebo 500mgx3 for 7 days

    Investigational medicinal product name
    metronidazole placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Metronidazole placebo 400mgx3 for 7 days

    Number of subjects in period 1
    		Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Started
    28
    28
    28
    Completed
    26
    26
    24
    Not completed
    2
    2
    4
         Adverse event, serious fatal
    -
    1
    -
         Consent withdrawn by subject
    1
    -
    2
         started antibiotic treatment for other condition
    -
    -
    1
         patient needed other intervention
    -
    -
    1
         panic attack before surgery
    1
    -
    -
         Protocol deviation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Surgical treatment with amoxicillin + metronidazole
    Reporting group description
    		 Surgical treatment with amoxicillin 500mgx3x7 + metronidazole 400mgx3x7

    Reporting group title
    Surgical treatment with metronidazole + phenoxymethylpenicilli
    Reporting group description
    		 Surgical treatment with metronidazole 400mgx3x7 + phenoxymethylpenicillin (800mgx2), x3x7

    Reporting group title
    Surgical treatment with placebo amoxicillin + metronidazole
    Reporting group description
    		 Surgical treatment with placebo tablets amoxicillin 500mg and 400mg metronidazole, 2 capsules 3 times daily.

    Reporting group values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole Total
    Number of subjects
    		 28 28 28 84
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 62.07 ( 17.8 ) 66.64 ( 16.6 ) 69.54 ( 13.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 18 19 15 52
        Male
    		 10 9 13 32

    End points

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    End points reporting groups
    Reporting group title
    Surgical treatment with amoxicillin + metronidazole
    Reporting group description
    		 Surgical treatment with amoxicillin 500mgx3x7 + metronidazole 400mgx3x7

    Reporting group title
    Surgical treatment with metronidazole + phenoxymethylpenicilli
    Reporting group description
    		 Surgical treatment with metronidazole 400mgx3x7 + phenoxymethylpenicillin (800mgx2), x3x7

    Reporting group title
    Surgical treatment with placebo amoxicillin + metronidazole
    Reporting group description
    		 Surgical treatment with placebo tablets amoxicillin 500mg and 400mg metronidazole, 2 capsules 3 times daily.

    Primary: Peri-implant pocket reduction at 6 months

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    End point title
    		 Peri-implant pocket reduction at 6 months
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to 6 months
    End point values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects analysed
    26 [1]
    26 [2]
    24 [3]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    -3.23 ( 1.78 )
    -3.26 ( 1.54 )
    -2.81 ( 2.00 )
    Notes
    [1] - Number of implants = 40
    [2] - Number of implants = 35
    [3] - Number of implants = 29
    Statistical analysis title
    		 Mean probing depth changes (mm) between groups
    Statistical analysis description
    Mean probing depth changes (mm) between baseline and 6 months and between groups
    Comparison groups
    Surgical treatment with amoxicillin + metronidazole v Surgical treatment with metronidazole + phenoxymethylpenicilli v Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.458
    Method
    		 Kruskal-wallis
    Confidence interval

    Primary: Peri-implant pocket reduction at 12 months

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    End point title
    		 Peri-implant pocket reduction at 12 months
    End point description
    End point type
    Primary
    End point timeframe
    From baseline to 12 months
    End point values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects analysed
    26 [4]
    26 [5]
    24 [6]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    -3.38 ( 1.72 )
    -3.29 ( 1.47 )
    -3.07 ( 2.23 )
    Notes
    [4] - Number of implants = 40
    [5] - Number of implants = 35
    [6] - Number of implants = 29
    Statistical analysis title
    		 Mean probing depth changes (mm) between groups
    Statistical analysis description
    Mean probing depth changes (mm) between baseline and 12 months and between groups
    Comparison groups
    Surgical treatment with amoxicillin + metronidazole v Surgical treatment with metronidazole + phenoxymethylpenicilli v Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.565
    Method
    		 Kruskal-wallis
    Confidence interval

    Primary: Marginal bone level stability at baseline

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    End point title
    		 Marginal bone level stability at baseline
    End point description
    End point type
    Primary
    End point timeframe
    Baseline
    End point values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects analysed
    26 [7]
    26 [8]
    24 [9]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    5.1 ( 2.3 )
    5.1 ( 1.8 )
    5.1 ( 2.0 )
    Notes
    [7] - Number of implants = 40
    [8] - Number of implants = 35
    [9] - Number of implants = 29
    Statistical analysis title
    		 Mean marginal bone level (mm) between groups
    Statistical analysis description
    Mean marginal bone level (mm) between groups at baseline
    Comparison groups
    Surgical treatment with amoxicillin + metronidazole v Surgical treatment with metronidazole + phenoxymethylpenicilli v Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.926
    Method
    		 Wilcoxon signed rank test
    Confidence interval

    Primary: Marginal bone level stability Postoperatively

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    End point title
    		 Marginal bone level stability Postoperatively
    End point description
    End point type
    Primary
    End point timeframe
    Postoperatively
    End point values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects analysed
    26 [10]
    26 [11]
    24 [12]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    5.2 ( 2.3 )
    5.2 ( 1.8 )
    5.4 ( 2.0 )
    Notes
    [10] - Number of implants = 40
    [11] - Number of implants = 35
    [12] - Number of implants = 29
    Statistical analysis title
    		 Mean marginal bone level (mm) between groups
    Statistical analysis description
    Mean marginal bone level (mm) between groups - Postoperatively
    Comparison groups
    Surgical treatment with amoxicillin + metronidazole v Surgical treatment with metronidazole + phenoxymethylpenicilli v Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.76
    Method
    		 Wilcoxon signed rank test
    Confidence interval

    Primary: Marginal bone level stability at 12 months

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    End point title
    		 Marginal bone level stability at 12 months
    End point description
    End point type
    Primary
    End point timeframe
    at 12 months
    End point values
    		 Surgical treatment with amoxicillin + metronidazole Surgical treatment with metronidazole + phenoxymethylpenicilli Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects analysed
    26 [13]
    26 [14]
    24 [15]
    Units: millimetre(s)
        arithmetic mean (standard deviation)
    4.2 ( 2.2 )
    4.9 ( 1.8 )
    5.1 ( 2.0 )
    Notes
    [13] - Number of implants = 40
    [14] - Number of implants = 35
    [15] - Number of implants = 29
    Statistical analysis title
    		 Mean marginal bone level (mm) between groups
    Statistical analysis description
    Mean marginal bone level (mm) between groups at 12 months
    Comparison groups
    Surgical treatment with amoxicillin + metronidazole v Surgical treatment with metronidazole + phenoxymethylpenicilli v Surgical treatment with placebo amoxicillin + metronidazole
    Number of subjects included in analysis
    76
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.118
    Method
    		 Wilcoxon signed rank test
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From 2015-04-14 to 2022-05-27
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 Free text
    Dictionary version
    n/a
    Reporting groups
    Reporting group title
    All study subjects
    Reporting group description
    		 -

    Serious adverse events
    		 All study subjects
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 84 (8.33%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Adenocarcinoma
    Additional description: Malignant tumor
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac arrest
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Reproductive system and breast disorders
    Testicular cancer
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Primary biliary cholangitis
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Renal and urinary disorders
    Bladder cancer
    Additional description: Urine bladder cancer
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 All study subjects
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 84 (42.86%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences all number
    2
    Panic attack
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Waldenstrom's macroglobulinaemia
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences all number
    2
    Pain
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences all number
    3
    Swelling
         subjects affected / exposed
    7 / 84 (8.33%)
         occurrences all number
    7
    Haematoma
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Sinus disorder
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences all number
    2
    Obstruction
    Additional description: Obstruction sublingual caruncle
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Gastrointestinal disorders
    Taste disorder
    Additional description: Bad taste
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Flatulence
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences all number
    2
    Abdominal pain
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences all number
    3
    Nausea
         subjects affected / exposed
    5 / 84 (5.95%)
         occurrences all number
    5
    Diarrhoea
         subjects affected / exposed
    11 / 84 (13.10%)
         occurrences all number
    11
    Heartburn
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Appetite disorder
    Additional description: No appetite
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences all number
    3
    Skin and subcutaneous tissue disorders
    Rash
    Additional description: Skin rash
         subjects affected / exposed
    2 / 84 (2.38%)
         occurrences all number
    2
    Itching
         subjects affected / exposed
    3 / 84 (3.57%)
         occurrences all number
    3
    Allergy
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1
    Infections and infestations
    Cold like symptoms
         subjects affected / exposed
    1 / 84 (1.19%)
         occurrences all number
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    12 Dec 2016
    Closing of one study center (Folktandvården Skanstull). Recruitement of patients only made to study center in Uppsala.
    11 Apr 2018
    Changes in inclusioncriteria 1 and 6. Change in exclusioncriteria 2. Changes made in follow-up visits (Visit 1 and Visit 2 became Visit 1. Visit 5 was removed.)
    18 Aug 2020
    Extension made on shelf-life for placebo capsules from 24 months to 36 months.

    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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