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    Clinical Trial Results:
    Treatment of multi-organ bodily distress syndrome. A double-blinded placebo controlled trial of the effect of Imipramine (STreSS-3)

    Summary
    EudraCT number
    		 2011-004294-87
    Trial protocol
    		 DK  
    Global end of trial date
    01 May 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    28 Jun 2017
    First version publication date
    28 Jun 2017
    Other versions
    Summary report(s)
    		 Eudract 2011-004294-87 Imipramine versus placebo

    Trial information

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    Trial identification
    Sponsor protocol code
    1,2
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01518634
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 The Danish Health Authority: 2011100742, The Ethics Committee of the Central Denmark Region: 20110210, The Danish Data Protection Agency: 2007-58-0010
    Sponsors
    Sponsor organisation name
    Research Clinic for Functional Disorders and Psychosomatics, Per Fink
    Sponsor organisation address
    Noerrebrogde 33, Aarhus, Denmark, 8000
    Public contact
    Clinical Trial Information, Research Clinic for Functional Disorders and Psychosomatics, +45 89494310, aarhus.ffl@rm.dk
    Scientific contact
    Clinical Trial Information, Research Clinic for Functional Disorders and Psychosomatics, +45 89494310, aarhus.ffl@rm.dk
    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
    10 Jan 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    01 May 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    01 May 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of this study is to test the effect of Imipramine in patients with multi-organ Bodily Distress Syndrome (BDS). BDS is a unifying diagnosis that encompasses a group of closely related conditions such as somatisation disorder, fibromyalgia, irritable bowel syndrome and chronic fatigue syndrome. The project consists of a double-blinded placebo controlled trial of treatment with the tricyclic antidepressant Imipramine in dosages of 25-75 mg. Primary outcome is patient-rated improvement measured by Clinical Global Improvement Scale (CGI-I). Secondary outcome is functional level (physical, mental and social) measured by the SF-36.
    Protection of trial subjects
    The diagnosis was established by an MD after a thorough physical and psychological assessment including diagnostic interview (Schedules for Clinical Assessment in Neuropsychiatry), physical examination, blood test, ECG, and a close review of all medical records. Up to eight tablets of 500 mg paracetamol were available daily as escape medication.
    Background therapy
    		 Up to eight tablets of 500 mg paracetamol were available daily as escape medication
    Evidence for comparator
    		 placebo
    Actual start date of recruitment
    30 Jan 2012
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Scientific research
    Long term follow-up duration
    		 2 Years
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Denmark: 138
    Worldwide total number of subjects
    138
    EEA total number of subjects
    138
    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)
    138
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From January 30, 2012 to November 24, 2014, consecutively referred patients with multiple, long-lasting symptoms were screened for inclusion in a university hospital setting at The Research Clinic for Functional Disorders, Aarhus University Hospital, Denmark.

    Pre-assignment
    Screening details
    		 A total of 551 consecutively referred patients were screened. 418 patients fulfilled diagnostic criteria for multi-organ BDS. 161 excluded. Primary reasons for exclusion hereafter were psychiatric disorders demanding treatment or ongoing pain medication. 118 declined to participate.

    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, Carer, Assessor
    Blinding implementation details
    Coded (numbered) packs of study drug and matched placebo were produced according to the randomisation schedule by the hospital pharmacy. Capsules of 10 mg and 25 mg imipramine and matched placebo for 25 mg were provided by Takeda Pharma A/S; placebo for 10 mg was produced by the hospital pharmacy. The capsules of 10 mg imipramine along with pharmacy-produced 10 mg placebos were both over-encapsulated by the hospital pharmacy to ensure identical appearance.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Imipramine
    Arm description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.
    Arm type
    		 Experimental

    Investigational medicinal product name
    imipramine
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study drugs were administered during the pre-intervention period.

    Arm title
    		 Placebo
    Arm description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.
    Arm type
    		 Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    No study drugs were administered during the pre-intervention period.

    Number of subjects in period 1 [1]
    		Imipramine Placebo
    Started
    65
    60
    Completed
    57
    53
    Not completed
    8
    7
         Adverse event, non-fatal
    4
    3
         practical issues
    -
    1
         regret participation
    2
    -
         Protocol deviation
    2
    3
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: The patients included in the analysis are the ones who received at least one dose of study drug

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Imipramine
    Reporting group description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.

    Reporting group values
    		 Imipramine Placebo Total
    Number of subjects
    		 65 60 125
    Age categorical
    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)
    		 65 60 125
        From 65-84 years
    		 0 0 0
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 53 41 94
        Male
    		 12 19 31

    End points

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    End points reporting groups
    Reporting group title
    Imipramine
    Reporting group description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.

    Reporting group title
    Placebo
    Reporting group description
    		 After wash-out, the patients started treatment with 10 mg imipramine or matched placebo, increasing to 25 mg after one week. Drugs and placebos were hereafter titrated to a maximum of 75 mg once daily. Depending on tolerance, dosages were maintained at this level during the remaining part of the study, or reduced if required. Total enrolment time was 19 weeks from inclusion until two weeks after the final dose of study drug.

    Primary: Clinical global improvement scale CGI

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    End point title
    		 Clinical global improvement scale CGI
    End point description
    Response to “How do you consider your health status now compared with when you first came to the clinic?” with 5 respons categories
    End point type
    Primary
    End point timeframe
    from baseline to after 10 weeks of minimum 25 mg study drug
    End point values
    		 Imipramine Placebo
    Number of subjects analysed
    63
    57
    Units: points
        much worse
    1
    1
        worse
    4
    11
        unchanged
    25
    31
        better
    22
    14
        much better
    11
    0
    Statistical analysis title
    		 Porportional odds model
    Statistical analysis description
    Analysis of the main outcome, CGI score, was based on the three outcome groupings comparing imipramine with placebo using an unadjusted proportional odds model. We reported as the main result the analysis based on data available in the ITT population.
    Comparison groups
    Imipramine v Placebo
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    3.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.6
         upper limit
    		 6.8
    Variability estimate
    Standard deviation
    Dispersion value
    0.001

    Secondary: SF-36 PCS

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    End point title
    		 SF-36 PCS
    End point description
    Physical component summary SF-36
    End point type
    Secondary
    End point timeframe
    from baseline to after 10 weeks of minimum 25 mg study drug
    End point values
    		 Imipramine Placebo
    Number of subjects analysed
    63
    57
    Units: points
    63
    57
    Statistical analysis title
    		 Differnces between groups at endpoint
    Comparison groups
    Placebo v Imipramine
    Number of subjects included in analysis
    120
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.022
    Method
    		 Regression, Linear
    Parameter type
    		 Median difference (final values)
    Point estimate
    3.9
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.6
         upper limit
    		 7.2
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    from the first dose of study drug until 2 weeks after the last dose of study drug
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Reporting groups
    Reporting group title
    imipramine
    Reporting group description
    		 -

    Reporting group title
    placebo
    Reporting group description
    		 -

    Serious adverse events
    		 imipramine placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 65 (0.00%)
    0 / 60 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 imipramine placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    36 / 65 (55.38%)
    12 / 60 (20.00%)
    Nervous system disorders
    moderate adverse events
         subjects affected / exposed
    36 / 65 (55.38%)
    12 / 60 (20.00%)
         occurrences all number
    36
    12

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28408193
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