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    Clinical Trial Results:
    A multi-centre, randomized, parallel-group, single blind Phase II trial to evaluate the pharmacokinetics and PKPD relationship of trazodone after single and repeated oral doses in children from 2 to ≤ 17 years of age, suffering from insomnia, with autism, intellectual disability or attention deficit hyperactivity disorder (ADHD)

    Summary
    EudraCT number
    		 2018-001166-42
    Trial protocol
    		 ES   IT  
    Global end of trial date
    08 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions
    Summary report(s)
    		 Study Report Synopsis

    Trial information

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    Trial identification
    Sponsor protocol code
    152PO17433
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Aziende Chimiche Riunite Angelini Francesco ACRAF S.p.A (Angelini S.p.A)
    Sponsor organisation address
    Viale Amelia, 70, Rome, Italy, 00181
    Public contact
    Valeria Tellone-Study Manager, Aziende Chimiche Riunite Angelini Francesco ACRAF S.p.A (Angelini S.p.A), 0039 0691045306, valeria.tellone@angelinipharma.com
    Scientific contact
    Valeria Tellone-Study Manager, Aziende Chimiche Riunite Angelini Francesco ACRAF S.p.A (Angelini S.p.A), 0039 0691045306, valeria.tellone@angelinipharma.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    Yes
    EMA paediatric investigation plan number(s)
    		 EMEA-002142-PIP01-17
    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
    08 Oct 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Oct 2021
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The primary objective of this study is to assess the PK of trazodone after single and repeated doses in patients aged from 2 to ≤ 17 years. Last subject last visit was 23/12/2019.
    Protection of trial subjects
    A favourable opinion of the relevant IECs was obtained before the start of the study. For each patient, a written ICF (signed by the parent(s)) and a written assent form signed and dated by the patients, if applicable, was obtained. Children received adequate written/oral information on the study, in accordance with age and maturity level.
    Background therapy
    		 Use of prior medications was reported for 3 patients (17%). Three patients (17%) used melatonin; of which 2 (11%) also used clonidine. Use of concomitant medications was reported for 9 patients (50%). The most frequently reported concomitant medications were in the group of psychoanaleptics (6 patients, 33%), such as lisdexamfetamine (3 patients, 17%) and methylphenidate hydrochloride (2 patients, 11%); all other concomitant medications were reported for 1 patient only.
    Evidence for comparator
    		 Not applicable
    Actual start date of recruitment
    22 Feb 2019
    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
    Spain: 5
    Country: Number of subjects enrolled
    Italy: 14
    Worldwide total number of subjects
    19
    EEA total number of subjects
    19
    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)
    12
    Adolescents (12-17 years)
    7
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 After consent from the parent(s) had been obtained and assent from the patients had been documented, the patients were screened for eligibility at the screening visit.

    Pre-assignment
    Screening details
    		 At the start of the screening period, an actigraphy device was delivered to the patient and used for at least 1 week to ensure that the patient had become familiarised with device use before the start of the treatment phase. Sleep latency and total sleeping time were recorded by actigraphy starting from 3 consecutive days before Visit 1.

    Period 1
    Period 1 title
    PERIOD 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    The study was conducted in a single-blind fashion, i.e., the investigator and other centre staff performing safety and clinical evaluations did not know which patients were receiving which dose of trazodone. To ensure this condition, the trazodone solution for administration was prepared out of sight (e.g., in a separate room) of the investigator and other centre staff.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ARM 1 - 0.25 mg/Kg/day
    Arm description
    		 Patients were treated with 0.25 mg/kg/day from Days 1 to Day 10.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone Hydrochloride
    Investigational medicinal product code
    039
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients from 2 to 5 years (inclusive) received trazodone oral drops 1.5%, and patients from 6 to 17 years (inclusive) received trazodone oral drops 3%. Patients received trazodone once daily in the evening, approximately 30 minutes before the usual bedtime, for a total of 10 days. The intake was to occur in a fed state; a list of recommended snacks to maintain the fed state was included in the study manual. Trazodone oral drops were diluted in approximately 20 mL of sugar water (half a teaspoon of sugar, corresponding to approximately 2 g, dissolved in 20 mL water) or red orange juice by the parent(s) immediately before administration. The diluted solution was to be administered within 30 minutes of preparation. Immediately after IMP intake, patients were requested to swallow an additional 100 mL (from 2 through 6 years) or 200 mL (from 7 through 17 years) of water or red orange juice to ensure complete intake of any IMP remaining in the oral cavity.

    Arm title
    		 ARM 2 - 0.4 mg/Kg/day
    Arm description
    		 Patients were treated with 0.4 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.4 mg/kg/day on Days 4 through 10)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone Hydrochloride
    Investigational medicinal product code
    039
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients from 2 to 5 years (inclusive) received trazodone oral drops 1.5%, and patients from 6 to 17 years (inclusive) received trazodone oral drops 3%. Patients received trazodone once daily in the evening, approximately 30 minutes before the usual bedtime, for a total of 10 days. The intake was to occur in a fed state; a list of recommended snacks to maintain the fed state was included in the study manual. Trazodone oral drops were diluted in approximately 20 mL of sugar water (half a teaspoon of sugar, corresponding to approximately 2 g, dissolved in 20 mL water) or red orange juice by the parent(s) immediately before administration. The diluted solution was to be administered within 30 minutes of preparation. Immediately after IMP intake, patients were requested to swallow an additional 100 mL (from 2 through 6 years) or 200 mL (from 7 through 17 years) of water or red orange juice to ensure complete intake of any IMP remaining in the oral cavity.

    Arm title
    		 ARM3 - 0.5 mg/kg/day
    Arm description
    		 Patients were treated with 0.5 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.5 mg/kg/day on Days 4 through 10)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone Hydrochloride
    Investigational medicinal product code
    039
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    Patients from 2 to 5 years (inclusive) received trazodone oral drops 1.5%, and patients from 6 to 17 years (inclusive) received trazodone oral drops 3%. Patients received trazodone once daily in the evening, approximately 30 minutes before the usual bedtime, for a total of 10 days. The intake was to occur in a fed state; a list of recommended snacks to maintain the fed state was included in the study manual. Trazodone oral drops were diluted in approximately 20 mL of sugar water (half a teaspoon of sugar, corresponding to approximately 2 g, dissolved in 20 mL water) or red orange juice by the parent(s) immediately before administration. The diluted solution was to be administered within 30 minutes of preparation. Immediately after IMP intake, patients were requested to swallow an additional 100 mL (from 2 through 6 years) or 200 mL (from 7 through 17 years) of water or red orange juice to ensure complete intake of any IMP remaining in the oral cavity.

    Number of subjects in period 1
    		ARM 1 - 0.25 mg/Kg/day ARM 2 - 0.4 mg/Kg/day ARM3 - 0.5 mg/kg/day
    Started
    3
    6
    10
    Completed
    3
    5
    10
    Not completed
    0
    1
    0
         QT prolongation
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    PERIOD 1 (overall period)
    Reporting group description
    		 -

    Reporting group values
    		 PERIOD 1 (overall period) Total
    Number of subjects
    		 19 19
    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)
    		 12 12
        Adolescents (12-17 years)
    		 7 7
        Adults (18-64 years)
    		 0 0
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 10.1 ± 3.69 -
    Gender categorical
    Units: Subjects
        Female
    		 2 2
        Male
    		 17 17
    Subject analysis sets

    Subject analysis set title
    PK analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who had been randomly assigned to a treatment arm, taken at least 1 dose of the IMP, and at least 1 postdose blood sample that was available and evaluable

    Subject analysis sets values
    		 PK analysis set
    Number of subjects
    18
    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)
    11
        Adolescents (12-17 years)
    7
        Adults (18-64 years)
    0
        From 65-84 years
    0
        85 years and over
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    10.1 ± 3.69
    Gender categorical
    Units: Subjects
        Female
        Male

    End points

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    End points reporting groups
    Reporting group title
    ARM 1 - 0.25 mg/Kg/day
    Reporting group description
    		 Patients were treated with 0.25 mg/kg/day from Days 1 to Day 10.

    Reporting group title
    ARM 2 - 0.4 mg/Kg/day
    Reporting group description
    		 Patients were treated with 0.4 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.4 mg/kg/day on Days 4 through 10)

    Reporting group title
    ARM3 - 0.5 mg/kg/day
    Reporting group description
    		 Patients were treated with 0.5 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.5 mg/kg/day on Days 4 through 10)

    Subject analysis set title
    PK analysis set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    All patients who had been randomly assigned to a treatment arm, taken at least 1 dose of the IMP, and at least 1 postdose blood sample that was available and evaluable

    Primary: AUCss

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    End point title
    		 AUCss [1]
    End point description
    The primary objective of this study was to assess the PK of trazodone after single and repeated doses in patients aged from 2 to ≤17 years by means of the prior estimation of oral clearance, intercompartmental clearance, apparent volume of distribution, and absorption rate constant.
    End point type
    Primary
    End point timeframe
    At Steady state (10 days)
    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: Descriptive statistics were applied
    End point values
    		 ARM 1 - 0.25 mg/Kg/day ARM 2 - 0.4 mg/Kg/day ARM3 - 0.5 mg/kg/day
    Number of subjects analysed
    3
    5
    10
    Units: mg*h/l
        median (confidence interval 90%)
    1399.8 (1150.9 to 1620.4)
    3081.8 (2757.2 to 4444.2)
    3184.9 (1471.9 to 6260.5)
    No statistical analyses for this end point

    Primary: Cmax, ss

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    End point title
    		 Cmax, ss
    End point description
    The primary objective of this study was to assess the PK of trazodone after single and repeated doses in patients aged from 2 to ≤17 years.
    End point type
    Primary
    End point timeframe
    At Steadystate (10 days)
    End point values
    		 ARM 1 - 0.25 mg/Kg/day ARM 2 - 0.4 mg/Kg/day ARM3 - 0.5 mg/kg/day
    Number of subjects analysed
    3
    5
    10
    Units: ng/ml
        median (confidence interval 90%)
    192.1 (113.6 to 217.6)
    309.4 (279.1 to 343.2)
    333.7 (165.9 to 564.6)
    Statistical analysis title
    		 Predicted PK parameter estimation
    Comparison groups
    ARM 1 - 0.25 mg/Kg/day v ARM 2 - 0.4 mg/Kg/day v ARM3 - 0.5 mg/kg/day
    Number of subjects included in analysis
    18
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    Method
    Parameter type
    		 median
    Point estimate
    1399.8
    Confidence interval
         level
    		 90%
         sides
    2-sided
         lower limit
    		 1150.9
         upper limit
    		 1620.4

    Primary: AUC

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    End point title
    		 AUC [2]
    End point description
    The primary objective of this study was to assess the PK of trazodone after single and repeated doses in patients aged from 2 to ≤17 years.
    End point type
    Primary
    End point timeframe
    Single dose
    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: Descriptive statistics were applied
    End point values
    		 ARM 1 - 0.25 mg/Kg/day ARM 2 - 0.4 mg/Kg/day ARM3 - 0.5 mg/kg/day
    Number of subjects analysed
    3
    5
    10
    Units: mg*h/l
        median (confidence interval 90%)
    1399.8 (1150.9 to 1620.4)
    2947.9 (2683.1 to 4194.9)
    3008.5 (1404.1 to 5649.7)
    No statistical analyses for this end point

    Primary: Cmax

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    End point title
    		 Cmax [3]
    End point description
    The primary objective of this study was to assess the PK of trazodone after single and repeated doses in patients aged from 2 to ≤17 years.
    End point type
    Primary
    End point timeframe
    Single dose
    Notes
    [3] - 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: Descriptive statistics were applied
    End point values
    		 ARM 1 - 0.25 mg/Kg/day ARM 2 - 0.4 mg/Kg/day ARM3 - 0.5 mg/kg/day
    Number of subjects analysed
    3
    5
    10
    Units: ng/ml
        median (confidence interval 90%)
    192.1 (113.6 to 217.6)
    297.3 (271.2 to 332.0)
    304.6 (157.2 to 525.2)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The investigator carefully monitored the patients’ symptoms and/or signs, either spontaneously reported or detected, throughout the whole study period from the signing and dating of the ICF up to the last scheduled visit.
    Adverse event reporting additional description
    Treatment-Emergent Adverse Event (TEAE) are considered.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    ARM 1
    Reporting group description
    		 Arm 1: Patients treated with Trazodone Hydrochloride 0.25 mg/kg/day from Days 1 to Day 10

    Reporting group title
    ARM 2
    Reporting group description
    		 Patients treated with Trazodone Hydrochloride 0.4 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.4 mg/kg/day on Days 4 through 10)

    Reporting group title
    ARM 3
    Reporting group description
    		 Patients treated with Trazodone Hydrochloride 0.5 mg/kg/day (0.25 mg/kg/day on Days 1 through 3 and 0.5 mg/kg/day on Days 4 through 10)

    Serious adverse events
    		 ARM 1 ARM 2 ARM 3
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    0 / 10 (0.00%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 ARM 1 ARM 2 ARM 3
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    2 / 10 (20.00%)
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 3 (0.00%)
    1 / 5 (20.00%)
    0 / 10 (0.00%)
         occurrences all number
    0
    6
    0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Cough
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Oropharyngeal pain
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Rush erythematous
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    1
    Metabolism and nutrition disorders
    Decreased appetite
         subjects affected / exposed
    0 / 3 (0.00%)
    0 / 5 (0.00%)
    1 / 10 (10.00%)
         occurrences all number
    0
    0
    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 2018
    Substantial - Spain. Linked to protocol 2.0 to harmonize study in the two countries
    18 Feb 2019
    Substantial - Italy. To harmonize IMPD document in the two countries, after request from AEMPS
    07 Nov 2019
    Substantial - Italy and Spain. New IMPD generated.
    09 Apr 2020
    Substantial - Italy and Spain. Halt of enrollment due to COVID-19
    27 Apr 2020
    Substantial - Italy and Spain. Linked to protocol 3.0: modification of interim analysis

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    20 Mar 2020
    After a study-specific risk assessment, in which subject safety and data integrity were a priority, Angelini S.p.A. decided to temporarily stop the enrolment in the clinical trial 152PO17433, especially taking into consideration the fragile population to be included. There is to underline that no patients were on-going in the study at that time; last patient was screened 06/MAR/2020 and dropped-out 12/MAR/2020 as for relevant site’s hospital board request to stop all unnecessary study visits.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    This study was prematurely stopped due to difficulties in enrolling patients. In addition, interim analysis results revealed that an increase of the dose would have been needed to obtain the desired effect.
    For support, Contact us.
    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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