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    Clinical Trial Results:
    Efficacy and safety of low doses of trazodone in patients affected by painful diabetic neuropathy: randomized, controlled, pilot study.

    Summary
    EudraCT number
    		 2016-002772-27
    Trial protocol
    		 CZ   HU   PL  
    Global end of trial date
    09 Aug 2018

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2019
    First version publication date
    30 Aug 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    039(B)PO16143
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    A.C.R.A.F. SpA (Angelini SpA)
    Sponsor organisation address
    Piazzale della Stazione s.n.c., S.Palomba-Pomezia (Rome), Italy, 00071
    Public contact
    Study Manager, A.C.R.A.F. SpA (Angelini SpA), 0039 0691045349 , p.lipone@angelini.it
    Scientific contact
    Study Manager, A.C.R.A.F. SpA (Angelini SpA), 0039 0691045349 , p.lipone@angelini.it
    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
    29 Jul 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    09 Aug 2018
    Global end of trial reached?
    Yes
    Global end of trial date
    09 Aug 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To collect preliminary information on the effect of low doses of trazodone on pain intensity in patients with painful diabetic neuropathy after 8-week treatment period.
    Protection of trial subjects
    No specific measures are provided. In case of ineffective treatment the Investigator can administer alternative drugs and the patients discontinue study.
    Background therapy
    		 Gabapentin was used in this study as “background therapy” in order to assure an effective pharmacological treatment, recommended as first line in painful diabetic neuropathy, to all patients which were enrolled in the trial. It was administered in open-label conditions to all patients enrolled in the study together with the investigational drug. A slow titration scheduling - 100 mg, 300 mg, 400 mg capsule (Neurontin®, Pfizer - was applied in order to better control the possible side effects when co-administered with trazodone. The increasing of dosage was implemented at each visit in accordance with the scheduling regimen.
    Evidence for comparator
    		 A placebo arm was foreseen by the study protocol in order to facilitate a clear assessment of the clinical relevance of the efficacy and safety of trazodone when coadministered with gabapentin [EMA/CHMP/970057/2011]
    Actual start date of recruitment
    16 May 2017
    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
    Poland: 73
    Country: Number of subjects enrolled
    Czech Republic: 50
    Country: Number of subjects enrolled
    Hungary: 19
    Worldwide total number of subjects
    142
    EEA total number of subjects
    142
    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)
    76
    From 65 to 84 years
    66
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment of 120 patients per treatment group (trazodone 30 mg, trazodone 60 and placebo) was planned. 142 patients were randomised and received allocated interventation from 16 May 2017 to 09 August 2018.

    Pre-assignment
    Screening details
    		 214 patients were enrolled. 72 patients were excluded: 64 for screening failure, 7 for PT requests to be excluded from the study and 1 for other reasons.

    Period 1
    Period 1 title
    PERIOD 1 (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Data analyst, Assessor
    Blinding implementation details
    The study was performed in double-blind conditions. In order to maintain the study double-blind conditions, the double-dummy technique was used. Thus, patients randomized in group 2 were co-administered with active oral solution and placebo oral solution.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Trazodone hydrochloride 6% oral solution - 60 mg
    Arm description
    		 Trazodone 20 mg (corresponding to 10 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 60 mg.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone hydrochloride 6% oral solution - 60 mg
    Investigational medicinal product code
    039
    Other name
    Trittico®
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    trazodone 20 mg (corresponding to 10 drops of trazodone hydrochloride 6% oral solution), three times a day, for 8-week treatment period. The total daily dose of trazodone administered to this group was 60 mg.

    Arm title
    		 Trazodone hydrochloride 6% oral solution - 30 mg
    Arm description
    		 Trazodone 10 mg (corresponding to 5 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 30 mg. less
    Arm type
    		 Experimental

    Investigational medicinal product name
    Trazodone hydrochloride 6% oral solution - 30 mg
    Investigational medicinal product code
    039
    Other name
    Trittico®
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    trazodone 10 mg (corresponding to 5 drops of trazodone hydrochloride 6% oral solution), three times a day, for 8-week treatment period. The total daily dose of trazodone administered to this group was 30 mg.

    Arm title
    		 Placebo
    Arm description
    		 Placebo, oral solution 10 drops three times a day, for 8-week treatment period.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution
    Routes of administration
    Oral use
    Dosage and administration details
    Placebo, oral solution 10 drops three times a day, for 8-week treatment period.

    Number of subjects in period 1
    		Trazodone hydrochloride 6% oral solution - 60 mg Trazodone hydrochloride 6% oral solution - 30 mg Placebo
    Started
    51
    43
    48
    Completed
    36
    33
    35
    Not completed
    15
    10
    13
         Consent withdrawn by subject
    5
    6
    2
         Adverse event, non-fatal
    -
    -
    3
         QTcF prolungation
    5
    3
    5
         Prohibited medication
    -
    -
    1
         Other reasons
    5
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Trazodone hydrochloride 6% oral solution - 60 mg
    Reporting group description
    		 Trazodone 20 mg (corresponding to 10 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 60 mg.

    Reporting group title
    Trazodone hydrochloride 6% oral solution - 30 mg
    Reporting group description
    		 Trazodone 10 mg (corresponding to 5 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 30 mg. less

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral solution 10 drops three times a day, for 8-week treatment period.

    Reporting group values
    		 Trazodone hydrochloride 6% oral solution - 60 mg Trazodone hydrochloride 6% oral solution - 30 mg Placebo Total
    Number of subjects
    		 51 43 48 142
    Age categorical
    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)
    		 26 23 27 76
        From 65-84 years
    		 25 20 21 66
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 63.2 ( 8.45 ) 62.1 ( 8.55 ) 62.3 ( 7.19 ) -
    Gender categorical
    Units: Subjects
        Female
    		 25 18 25 68
        Male
    		 26 25 23 74
    Subject analysis sets

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who took at least one dose of the study medication were included in the Safety population: 43 in the Trazodone 30 mg group, 51 in the Trazodone 60 mg group and 48 in the placebo group.

    Subject analysis set title
    Intention-to treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consisted of 141 patients (43 in the Trazodone 30 mg group, 50 in the Trazodone 60 mg group and 48 in the placebo group) who received allocated intervention and had baseline and at least one post-baseline BPI-SF evaluation.

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population consisted of 96 patients (31 in the Trazodone 30 mg group, 34 in the Trazodone 60 mg group and 31 in the placebo group) who completed the study period with no major protocol deviations and had baseline and V8 BPI-SF evaluation.

    Subject analysis sets values
    		 Safety population Intention-to treat (ITT) population Per Protocol (PP) population
    Number of subjects
    142
    141
    96
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    68
    67
    53
        Male
    74
    74
    43

    End points

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    End points reporting groups
    Reporting group title
    Trazodone hydrochloride 6% oral solution - 60 mg
    Reporting group description
    		 Trazodone 20 mg (corresponding to 10 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 60 mg.

    Reporting group title
    Trazodone hydrochloride 6% oral solution - 30 mg
    Reporting group description
    		 Trazodone 10 mg (corresponding to 5 drops of trazodone hydrochloride 6% oral solution), three times a day for 8 weeks. The total daily dose of trazodone administered to this group was 30 mg. less

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral solution 10 drops three times a day, for 8-week treatment period.

    Subject analysis set title
    Safety population
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    All randomized patients who took at least one dose of the study medication were included in the Safety population: 43 in the Trazodone 30 mg group, 51 in the Trazodone 60 mg group and 48 in the placebo group.

    Subject analysis set title
    Intention-to treat (ITT) population
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    The ITT population consisted of 141 patients (43 in the Trazodone 30 mg group, 50 in the Trazodone 60 mg group and 48 in the placebo group) who received allocated intervention and had baseline and at least one post-baseline BPI-SF evaluation.

    Subject analysis set title
    Per Protocol (PP) population
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    The PP population consisted of 96 patients (31 in the Trazodone 30 mg group, 34 in the Trazodone 60 mg group and 31 in the placebo group) who completed the study period with no major protocol deviations and had baseline and V8 BPI-SF evaluation.

    Primary: Change from baseline of the BPI-SF (item 5) at Visit 8 (day 56 ±2)

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    End point title
    		 Change from baseline of the BPI-SF (item 5) at Visit 8 (day 56 ±2)
    End point description
    The primary endpoint of the study was the efficacy of low doses of trazodone on pain intensity assessed as change from baseline of the BPI-SF 24-hour average pain score (item 5) at Visit 8 (day 56 ±2).
    End point type
    Primary
    End point timeframe
    The end point was evaluated at Visit 8 (day 56 ±2).
    End point values
    		 Trazodone hydrochloride 6% oral solution - 60 mg Trazodone hydrochloride 6% oral solution - 30 mg Placebo
    Number of subjects analysed
    50
    43
    48
    Units: pain score
        arithmetic mean (standard deviation)
    -2.6 ( 1.99 )
    -3.1 ( 1.74 )
    -2.5 ( 1.77 )
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    An analysis of covariance (ANCOVA) model including treatment as main effect and baseline as covariate was applied and the relevant least-square mean change from baseline to endpoint was estimated and compared between treatment groups.
    Comparison groups
    Trazodone hydrochloride 6% oral solution - 60 mg v Placebo
    Number of subjects included in analysis
    98
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.6272
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.87
         upper limit
    		 0.52
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    An analysis of covariance (ANCOVA) model including treatment as main effect and baseline as covariate was applied and the relevant least-square mean change from baseline to endpoint was estimated and compared between treatment groups.
    Comparison groups
    Trazodone hydrochloride 6% oral solution - 30 mg v Placebo
    Number of subjects included in analysis
    91
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.1179
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.57
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.3
         upper limit
    		 0.15
    Statistical analysis title
    		 ANCOVA
    Statistical analysis description
    An analysis of covariance (ANCOVA) model including treatment as main effect and baseline as covariate was applied and the relevant least-square mean change from baseline to endpoint was estimated and compared between treatment groups.
    Comparison groups
    Trazodone hydrochloride 6% oral solution - 60 mg v Trazodone hydrochloride 6% oral solution - 30 mg
    Number of subjects included in analysis
    93
    Analysis specification
    Post-hoc
    Analysis type
    		 other
    P-value
    		 = 0.267
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (net)
    Point estimate
    -0.4
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -1.12
         upper limit
    		 0.31

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs were monitored throughout the whole study period from the signature of the informed consent form up to the last visit scheduled in the protocol or ETV (if applicable).
    Adverse event reporting additional description
    After initiation of the study treatments, 133 AEs (TEAEs) were recorded: 53 TEAEs were reported by 27 patients in the trazodone 30 mg group, 35 TEAEs by 21 patients in the trazodone 60 mg group and 45 TEAEs by 20 patients in the placebo group.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Trazodone hydrochloride 6% oral solution - 60 mg
    Reporting group description
    		 Trazodone 20 mg (corresponding to 10 drops of trazodone hydrochloride 6% oral solution) three times a day for 8 weeks. The toatl daily dose of trazodone administered to this group was 60 mg.

    Reporting group title
    Trazodone hydrochloride 6% oral solution - 30 mg
    Reporting group description
    		 Trazodone 10 mg (corresponding to5 drops of trazodone hydrochloride 6% oral solution) three times a day for 8 weeks. The toatl daily dose of trazodone administered to this group was 30 mg.

    Reporting group title
    Placebo
    Reporting group description
    		 Placebo, oral solution 10 drops three times a day, for 8-week treatment period.

    Serious adverse events
    		 Trazodone hydrochloride 6% oral solution - 60 mg Trazodone hydrochloride 6% oral solution - 30 mg Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 43 (0.00%)
    0 / 48 (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
    		 Trazodone hydrochloride 6% oral solution - 60 mg Trazodone hydrochloride 6% oral solution - 30 mg Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    21 / 51 (41.18%)
    27 / 43 (62.79%)
    20 / 48 (41.67%)
    Investigations
    Electrocardiogram QT prolonged
         subjects affected / exposed
    5 / 51 (9.80%)
    4 / 43 (9.30%)
    8 / 48 (16.67%)
         occurrences all number
    5
    4
    8
    Nervous system disorders
    Disturbance in attention
         subjects affected / exposed
    3 / 51 (5.88%)
    0 / 43 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    4
    0
    0
    Dizziness
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 43 (0.00%)
    4 / 48 (8.33%)
         occurrences all number
    0
    0
    5
    Somnolence
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 43 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    0
    General disorders and administration site conditions
    Fatigue
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 43 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    0
    Peripheral swelling
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 43 (0.00%)
    3 / 48 (6.25%)
         occurrences all number
    2
    0
    3
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    2 / 51 (3.92%)
    0 / 43 (0.00%)
    0 / 48 (0.00%)
         occurrences all number
    2
    0
    0
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 51 (0.00%)
    3 / 43 (6.98%)
    2 / 48 (4.17%)
         occurrences all number
    0
    3
    3
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 51 (3.92%)
    2 / 43 (4.65%)
    0 / 48 (0.00%)
         occurrences all number
    2
    3
    0
    Metabolism and nutrition disorders
    Hypoglycaemia
         subjects affected / exposed
    0 / 51 (0.00%)
    0 / 43 (0.00%)
    1 / 48 (2.08%)
         occurrences all number
    0
    0
    3

    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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