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    Clinical Trial Results:
    Ethanol submandibular duct ligation for drooling in children with neurodisabilities

    Summary
    EudraCT number
    		 2021-004057-23
    Trial protocol
    		 NL  
    Global end of trial date
    31 Jan 2025

    Results information
    Results version number
    		 v1(current)
    This version publication date
    14 May 2025
    First version publication date
    14 May 2025
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    2021-12945
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Radboudumc
    Sponsor organisation address
    Geert Grooteplein Zuid 10, Nijmegen, Netherlands, 6525 GA
    Public contact
    Department of Otorhinolaryngology, Radboudumc, 0031 617377830, stijn.bekkers@radboudumc.nl
    Scientific contact
    dr. Stijn Bekkers, Radboudumc, 0031 617377830, stijn.bekkers@radboudumc.nl
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    31 Mar 2025
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Jan 2025
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jan 2025
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the feasibility of submandibular duct ligation right after intraductal ethanol infusion into the submandibular salivary gland
    Protection of trial subjects
    In accordance to section 10, subsection 4, of the WMO, the investigator will suspend the study if there is sufficient ground that continuation of the study will jeopardise subject health or safety. The investigator will notify the accredited METC without undue delay of a temporary halt including the reason for such an action. The study will be suspended pending a further positive decision by the accredited METC. The investigator will take care that all subjects are kept informed. All participants and/or their caregivers provided informed consent for participation in this study. Participants were able to step out of the study at any given moment. An insurance for subjects participating in medical research in the Radboudumc, that falls within the scope of the WMO, is available in accordance with the legal requirements of article 7 of the WMO and Medical Research (Human Subjects) Compulsory Insurance Decree of 23 June 2003.
    Background therapy
    		 The ethanol-SDL surgery was performed in a controlled setting under strict monitoring of the Medical Ethics Committee. All interventions were performed between 2021-2024 by the same surgeon, with 25 years of experience with submandibular gland surgery. A radiologist and pediatric surgeon with specific expertise in head and neck sclerotherapy were present during the whole procedure for potential consultation. Surgery The intervention was performed under general anesthesia. To prevent excessive post-operative swelling, patients received 1,5 mg / kilogram Di-Adreson-F aquosum per-operatively. Patients received 30mg / kilogram of cefazoline intravenously before the procedure. The floor of the mouth was infiltrated with 1% lidocaine with 1:100.000 epinephrine and incised parallel to the frenulum. The duct was identified, a suture was placed in the surrounding tissue to apply traction, and the duct was dissected for 1 cm to expose the ductal lumen. A 0.025-inch flexible cannula was placed inside the lumen and fixated with a suture. Dehydrated ethanol (EtOH) 96% was diluted with water-soluble contrast (Iomeron 300) in a ratio of 4:1, and 2-4ml of the solution (EtOH – Iomeron 300) was injected into each of the two submandibular ducts under digital subtraction sialography to assess the required injection volume and control for extravasation from the gland capsule. The duct was clipped with two vascular clips after retraction of the canula. A suction tube was present for retrograde leakage if necessary. The sublingual incision was closed with absorbable sutures. A schematic overview of the procedure was illustrated in figure 1. Post-operative care Patients were admitted for one-night post-operatively, and all patients received 500/125mg amoxicillin/clavulanic acid for 7 days and 1000mg paracetamol and 25mg diclofenac for 5 days post-operatively.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    26 Jul 2022
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 5
    Worldwide total number of subjects
    5
    EEA total number of subjects
    5
    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)
    1
    Adolescents (12-17 years)
    3
    Adults (18-64 years)
    1
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were selected from the intake consultation at the Saliva Control Clinic of the Radboud University Medical Center based on the in- and exclusion criteria, as stated in the manuscript. All participants and/or their caregivers provided written informed consent.

    Pre-assignment
    Screening details
    		 Inclusion criteria •Moderate to severe drooling •Aged ≥ 10 at time of surgery •Contra-indication for SMDR/rejection towards SMDR Exclusion criteria: •Progressive neurological disease •Medical history of salivary gland abnormalities •prior submandibular gland surgery •Contraindication for surgery or anesthesia •Other current drool treatment

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N.A.

    Arms
    Arm title
    		 Ethanol 2-duct ligation
    Arm description
    		 Participants received the ethanol 2-duct ligation surgery
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ethanol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Oral use
    Dosage and administration details
    Dehydrated ethanol (EtOH) 96% is diluted with water-soluble contrast (Iomeron 300) in ratio 4:1 and an estimated 2-3 mL of the solution (EtOH – Iomeron 300) is injected into the duct under digital subtraction sialography (DSS) in order to control for extravasation from the gland capsule. The maximum amount of Ethanol 96% is 4 mL per gland.

    Number of subjects in period 1
    		Ethanol 2-duct ligation
    Started
    5
    Completed
    5
    Period 2
    Period 2 title
    8 weeks post-surgery
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N.A.

    Arms
    Arm title
    		 Surgery arm
    Arm description
    		 Ethanol 2-duct ligation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ethanol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Oral use
    Dosage and administration details
    Dehydrated ethanol (EtOH) 96% is diluted with water-soluble contrast (Iomeron 300) in ratio 4:1 and an estimated 2-3 mL of the solution (EtOH – Iomeron 300) is injected into the duct under digital subtraction sialography (DSS) in order to control for extravasation from the gland capsule. The maximum amount of Ethanol 96% is 4 mL per gland.

    Number of subjects in period 2
    		Surgery arm
    Started
    5
    Completed
    5
    Period 3
    Period 3 title
    32 weeks post-surgery
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    N.A.

    Arms
    Arm title
    		 Surgery arm
    Arm description
    		 Ethanol 2-duct ligation
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ethanol
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for infusion
    Routes of administration
    Oral use
    Dosage and administration details
    Dehydrated ethanol (EtOH) 96% is diluted with water-soluble contrast (Iomeron 300) in ratio 4:1 and an estimated 2-3 mL of the solution (EtOH – Iomeron 300) is injected into the duct under digital subtraction sialography (DSS) in order to control for extravasation from the gland capsule. The maximum amount of Ethanol 96% is 4 mL per gland.

    Number of subjects in period 3
    		Surgery arm
    Started
    5
    Completed
    5

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 -

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 5 5
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 1 1
        Adolescents (12-17 years)
    		 3 3
        Adults (18-64 years)
    		 1 1
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 14 (11 to 18) -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 3 3

    End points

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    End points reporting groups
    Reporting group title
    Ethanol 2-duct ligation
    Reporting group description
    		 Participants received the ethanol 2-duct ligation surgery
    Reporting group title
    Surgery arm
    Reporting group description
    		 Ethanol 2-duct ligation
    Reporting group title
    Surgery arm
    Reporting group description
    		 Ethanol 2-duct ligation

    Primary: Feasibility

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    End point title
    		 Feasibility [1]
    End point description
    End point type
    Primary
    End point timeframe
    32 weeks post-surgery
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed on the descriptive statistics, as it was only a registration of the number of completed surgeries, and this study only included 1 arm, with 5 participants.
    End point values
    		 Ethanol 2-duct ligation Surgery arm
    Number of subjects analysed
    5
    5
    Units: Surgery completion
    5
    5
    No statistical analyses for this end point

    Primary: Safety

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    End point title
    		 Safety [2]
    End point description
    End point type
    Primary
    End point timeframe
    32 weeks post-surgery
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analyses were performed on the descriptive statistics, as it was only a registration of the number of serious adverse events, and this study only included 1 arm, with 5 participants.
    End point values
    		 Ethanol 2-duct ligation Surgery arm Surgery arm
    Number of subjects analysed
    5
    5
    5
    Units: Adverse Events
    0
    0
    0
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    32 weeks post-surgery
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    28
    Reporting groups
    Reporting group title
    Ethanol 2-duct ligation
    Reporting group description
    		 Participants received the ethanol 2-duct ligation surgery

    Serious adverse events
    		 Ethanol 2-duct ligation
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 5 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Ethanol 2-duct ligation
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 5 (40.00%)
    Gastrointestinal disorders
    gastro-enteritis
    Additional description: Hospital admission approximately 32-weeks post-surgery with 3 days of gastro-enteritis with fever.
         subjects affected / exposed [1]
    1 / 1 (100.00%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Allergic skin reaction
    Additional description: Mild allergic skin reaction to the antibiotic medication post-surgery
         subjects affected / exposed [2]
    1 / 1 (100.00%)
         occurrences all number
    1
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: The individual participant presented with a gastro-enteritis at 32-weeks post-surgery. This was not related to the exposure to the medical product. No other participants were exposed to gastro-enteritis.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: This was the only participant who appeared to have an allergic response to the antibiotic treatment. This was not directly related to the exposure to the medical product. No other participants had a similar allergic response to antibiotics.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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