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    Clinical Trial Results:
    Phase II-study Anti-inflammatory pulmonal therapy of CF-patients with Amitriptyline and Placebo - a randomised, double-blinded, placebo-controlled, cross over study

    Summary
    EudraCT number
    		 2006-002259-33
    Trial protocol
    		 DE  
    Global end of trial date
    31 Jul 2007

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Mar 2022
    First version publication date
    29 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    APA- II
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT00515229
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University Hospital Tübingen
    Sponsor organisation address
    Geissweg 3 , Tübingen, Germany, 72076
    Public contact
    Dr. med. Joachim Riethmüller, University Children´s Hospital Tübingen, +49 (0)201 723-3118, joachim.riethmueller@med.uni-tuebingen.de
    Scientific contact
    Dr. med. Joachim Riethmüller, University Children´s Hospital Tübingen, +49 (0)201 723-3118, joachim.riethmueller@med.uni-tuebingen.de
    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
    11 May 2009
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Jul 2007
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objective of the trial was to assess the therapeutic efficacy and safety of Amitriptyline in patients with Cystic Fibrosis (CF)
    Protection of trial subjects
    The Helsinki Declaration shall be applied to the clinical trial, as well as Good Clinical Practice (GCP) for conducting clinical trials of medicinal products within the European Community, in its current version. This is a scientific clinical study; the German Medicines Act (AMG) §40 is applicable without restrictions according to section §42. The protocol will be submitted to the Ethics Commission of the Tübingen University Clinical Centre, which is responsible for the principal investigator. In all further proceedings, the investigator at each participating centre will have to submit the protocol to the respective local Ethics Committee. At each individual centre, the study can only begin after the appropriate Ethics Committee has given its approval.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    10 Oct 2006
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Germany: 19
    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)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    19
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 All patients will be informed by the investigating physician about side effects and complications of the verum therapy prior to recruitment. All patients were examined after consent has been obtained by the investigating physician to their suitability for this study in terms of the inclusion and exclusion criteria (especially CYP2D6 genotyping).

    Pre-assignment
    Screening details
    		 21 cystic fibrosis (CF) patients were screened using the inclusion and exclusion criteria. Nineteen patients were finally enrolled (10 females, 9 males).

    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
    Blinding implementation details
    The manufacture and distribution of the study medication to the participating pharmacies is handled by the pharmacy facilities of the University of Tuebingen (Fr. Dr. Hartmann). The packaging, blinding, labelling and storage of the medicine at the pharmacy conforms to §10 of the AMG, according to a randomisation list that is only known to the pharmacy. Each individual capsule has a filling volume of 25 mg, 50 mg und 75 mg Amitriptyline and 25 mg placebo.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 Amitriptyline arm
    Arm description
    		 The patients were randomly allocated to three treatment groups receiving 2 doses of amitriptyline or placebo once daily for 28 days. Six patients received placebo, 25 mg and 50 mg amitriptyline, six patients received placebo, 25 mg and 75 mg amitriptyline, and another six patients received placebo, 50 mg and 75 mg of amitriptyline.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Amitriptyline
    Investigational medicinal product code
    549-18-8
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Patients received placebo, 25 mg/d and 50 mg/d amitriptyline, or placebo, 25 mg/d and 75 mg/d amitriptyline, or placebo, 50 mg/d and 75 mg/d amitriptyline.

    Arm title
    		 Placebo arm
    Arm description
    		 Patients received either placebo for 28 days and 25 mg of amitriptyline for 28 days and 50 mg for 28 days, or placebo for 28 days and 25 mg of amitriptyline for 28 days and 75 mg for 28 days, or placebo for 28 days and 50 mg of amitriptyline for 28 days and 75 mg for 28 days.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Corn starch
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    On day 1 of the study, Verum or placebo is administered oral one time daily. For two days at the beginning of each treatment a minimized dosage (25 mg) will be given. The quantity of study medication administered is 25mg, 50 mg or 75 mg of Amitriptyline, 25 mg of Placebo (corn starch). This corresponds to one capsule daily for 28 days.

    Number of subjects in period 1
    		Amitriptyline arm Placebo arm
    Started
    19
    19
    Completed
    18
    18
    Not completed
    1
    1
         Adverse event, non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 19 adult CF patients were randomly allocated to three treatment groups receiving amitriptyline once daily for 28 days at doses of 25 mg (n=7), 50 mg (n=8), or 75 mg (n=8) or placebo (n=13).

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 19 19
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 19 19
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 28.3 ( 10 ) -
    Gender categorical
    Units: Subjects
        Female
    		 10 10
        Male
    		 9 9

    End points

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    End points reporting groups
    Reporting group title
    Amitriptyline arm
    Reporting group description
    		 The patients were randomly allocated to three treatment groups receiving 2 doses of amitriptyline or placebo once daily for 28 days. Six patients received placebo, 25 mg and 50 mg amitriptyline, six patients received placebo, 25 mg and 75 mg amitriptyline, and another six patients received placebo, 50 mg and 75 mg of amitriptyline.

    Reporting group title
    Placebo arm
    Reporting group description
    		 Patients received either placebo for 28 days and 25 mg of amitriptyline for 28 days and 50 mg for 28 days, or placebo for 28 days and 25 mg of amitriptyline for 28 days and 75 mg for 28 days, or placebo for 28 days and 50 mg of amitriptyline for 28 days and 75 mg for 28 days.

    Subject analysis set title
    Amitriptyline 25 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The amitryptiline arm could be divided into 3 subgroups, depending on the dosing levels: 25 mg, 50 mg and 75 mg.

    Subject analysis set title
    Amitryptiline 50 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The amitryptiline arm could be divided into 3 subgroups, depending on the dosing levels: 25 mg, 50 mg and 75 mg.

    Subject analysis set title
    Amitryptiline 75 mg
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The amitryptiline arm could be divided into 3 subgroups, depending on the dosing levels: 25 mg, 50 mg and 75 mg.

    Primary: The primary outcome was the difference of forced expiratory volume in 1 sec (FEV1) at day 14 between amitriptyline and placebo.

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    End point title
    		 The primary outcome was the difference of forced expiratory volume in 1 sec (FEV1) at day 14 between amitriptyline and placebo. [1]
    End point description
    The primary outcome was the difference of FEV1 relative to placebo at day 14 in the per-protocol (PP) group measured by spirometry.
    End point type
    Primary
    End point timeframe
    14 days
    Notes
    [1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: More information about the statistical analysis can be found in the charts attached
    End point values
    		 Placebo arm Amitriptyline 25 mg Amitryptiline 50 mg Amitryptiline 75 mg
    Number of subjects analysed
    13
    7
    8
    8
    Units: percentage improvement
        arithmetic mean (standard deviation)
    -1.2 ( 4 )
    3 ( 4 )
    0.7 ( 3 )
    -0.7 ( 4 )
    Attachments
    		 Untitled (Filename: Efficacy results and statistical analysis.pdf)
    Statistical analysis title
    		 Statistical analysis amitryptiline 25 mg
    Comparison groups
    Placebo arm v Amitriptyline 25 mg
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.048
    Method
    		 t-test, 1-sided
    Confidence interval
    Statistical analysis title
    		 Statistical analysis amitryptiline 50 mg
    Comparison groups
    Placebo arm v Amitryptiline 50 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.28
    Method
    		 t-test, 1-sided
    Confidence interval
    Statistical analysis title
    		 Statistical analysis amitryptiline 75 mg
    Comparison groups
    Placebo arm v Amitryptiline 75 mg
    Number of subjects included in analysis
    21
    Analysis specification
    Post-hoc
    Analysis type
    		 non-inferiority
    P-value
    		 = 0.79
    Method
    		 t-test, 1-sided
    Confidence interval

    Secondary: Ceramide concentrations in respiratory epithelial cells

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    End point title
    		 Ceramide concentrations in respiratory epithelial cells [2]
    End point description
    Ceramide concentrations in respiratory epithelial cells were measured after 14 days of treatment
    End point type
    Secondary
    End point timeframe
    14 days after treatment
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: More information regarding the statistical analysis can be found in the charts attached
    End point values
    		 Amitriptyline arm
    Number of subjects analysed
    19
    Units: mg
        arithmetic mean (standard deviation)
    2 ( 1.55 )
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    28 days
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1
    Frequency threshold for reporting non-serious adverse events: 5%
    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Safety results regarding the non-serious adverse events can be found in the attached chart. No serious adverse events were reported in the study.

    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/1959019
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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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