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    Clinical Trial Results:
    THE EFFECT OF DIFLUNISAL ON FAMILIAL TRANSTHYRETIN AMYLOIDOSIS: An open label phase III extension study of the diflunisal trials (IND 68092 and DFNS01), and an open label observational study on previously untreated patients with familial transthyretin amyloidosis complicated by cardiomyopathy.

    Summary
    EudraCT number
    2014-001957-17
    Trial protocol
    SE  
    Global end of trial date
    04 Jun 2021

    Results information
    Results version number
    v1(current)
    This version publication date
    30 Jun 2022
    First version publication date
    30 Jun 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DFNS02
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Umeå University Hospital
    Sponsor organisation address
    Norrlands universitetssjukhus, Umeå, Sweden,
    Public contact
    Intissar Anan, Umeå University Hospital, 46 9078550000, intissar.anan@umu.se
    Scientific contact
    Intissar Anan, Umeå University Hospital, 46 9078550000, intissar.anan@umu.se
    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
    16 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    04 Jun 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    04 Jun 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To follow the development of neurological, nutritional and cardiac manifestations of transthyretin amyloidosis in patients treated by Diflunisal 250 mg twice daily. Primary end-points 1. changes in the Kumamoto scale 2. cardiac impairment measured by echocardiographic assessment of global systolic strain
    Protection of trial subjects
    The patient was safety evaluated 1 month, 3 months, 6 months, 9 months, 12 months, 18 months and 24 months. Blood samples: B-Hb, B- platelets, s-creatinine, liver enzymes (ASAT and ALAT, s- bilirubin and ALP). S- pro-BNP and Troponin. Detection and documentation of any events meeting the criteria and definition of an adverse event (AE) or serious adverse event (SAE). Clinically significant AEs considered by the investigator to be related to treatment were followed until resolved or considered stable. It was left to the investigator’s clinical judgment to determine whether an AE was related and of sufficient severity to require the subject’s removal from treatment or from the trial. A subject was also able to voluntarily withdraw from treatment due to what he or she perceived as an intolerable AE.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Sep 2015
    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
    Sweden: 32
    Worldwide total number of subjects
    32
    EEA total number of subjects
    32
    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)
    6
    From 65 to 84 years
    25
    85 years and over
    1

    Subject disposition

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    Recruitment
    Recruitment details
    A total of 32 patients were included at two sites, Umeå and Piteå. Study population was patient with transthyretin amyloidosis.

    Pre-assignment
    Screening details
    Patients who have participated in the DFNS01-study were asked to participate in this extensional study. New patients, who fulfilled the eligibility criteria were enrolled as well.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Not applicable
    Blinding used
    Not blinded

    Arms
    Arm title
    24 months of treatment with Diflunisal
    Arm description
    -
    Arm type
    Experimental

    Investigational medicinal product name
    Diflunisal
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    250 mg x 2 p.o

    Number of subjects in period 1
    24 months of treatment with Diflunisal
    Started
    32
    Completed
    19
    Not completed
    13
         Due to pandemic, did not come to study visit
    2
         Patients wish, did not come to study visits
    1
         Did not take study drug
    1
         Adverse event, non-fatal
    4
         Due to licence problem, no study drug
    3
         Did not fulfill inclusion criteria
    2

    Baseline characteristics

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

    Reporting group values
    Overall trial Total
    Number of subjects
    32 32
    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)
    0 0
        Adolescents (12-17 years)
    0 0
        Adults (18-64 years)
    6 6
        From 65-84 years
    25 25
        85 years and over
    1 1
        Not recorded
    0 0
    Gender categorical
    Units: Subjects
        Female
    11 11
        Male
    21 21

    End points

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    End points reporting groups
    Reporting group title
    24 months of treatment with Diflunisal
    Reporting group description
    -

    Subject analysis set title
    12 months treatment with Diflunisal
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    Primary endpoints measured at 12 months and 24 months of treatment with Diflunisal

    Primary: Changes in the Kumamoto scale

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    End point title
    Changes in the Kumamoto scale
    End point description
    End point type
    Primary
    End point timeframe
    Primary end-points will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    19
    27
    Units: Scale unit
        number (not applicable)
    32
    32
    Statistical analysis title
    Descriptive statistics
    Statistical analysis description
    Changes over time for primary end-points will be analysed by one-way ANOVA to detect significant changes over time.
    Comparison groups
    24 months of treatment with Diflunisal v 12 months treatment with Diflunisal
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [1]
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [1] - Kumamoto scale is measured at 0 month, 12 month and 24 months. Same subjects but different time frames.

    Primary: Cardiac impairment measured by echocardiographic assessment of global systolic strain

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    End point title
    Cardiac impairment measured by echocardiographic assessment of global systolic strain
    End point description
    End point type
    Primary
    End point timeframe
    Primary end-points will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    19
    27
    Units: Percent
    32
    32
    Statistical analysis title
    Descriptive statistics
    Statistical analysis description
    Changes over time for primary- and secondary end-points will be analysed by one-way ANOVA to detect significant changes over time.
    Comparison groups
    24 months of treatment with Diflunisal v 12 months treatment with Diflunisal
    Number of subjects included in analysis
    46
    Analysis specification
    Pre-specified
    Analysis type
    non-inferiority [2]
    P-value
    < 0.05
    Method
    Wilcoxon (Mann-Whitney)
    Confidence interval
    Notes
    [2] - Same subjects but different time frames.

    Secondary: Changes in nutritional status measured by the modified body mass index

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    End point title
    Changes in nutritional status measured by the modified body mass index
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary end-point will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    19
    26
    Units: mBMI
    32
    32
    No statistical analyses for this end point

    Secondary: changes in neurological impairment measured by the PND-score

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    End point title
    changes in neurological impairment measured by the PND-score
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary end-point will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    18
    26
    Units: PND-score
        number (not applicable)
    32
    32
    No statistical analyses for this end point

    Secondary: Cardiac impairment, echocardiographic measurement of septal thickness and blood pro-BNP concentration

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    End point title
    Cardiac impairment, echocardiographic measurement of septal thickness and blood pro-BNP concentration
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary end-point will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    27
    25
    Units: Mass/Vol
    32
    32
    No statistical analyses for this end point

    Secondary: Karnofsky performance scale

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    End point title
    Karnofsky performance scale
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary end-points will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    19
    26
    Units: KPS
        number (not applicable)
    32
    32
    No statistical analyses for this end point

    Secondary: Drug safety

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    End point title
    Drug safety
    End point description
    End point type
    Secondary
    End point timeframe
    Secondary end-point will be evaluated at 12 months and the end of the 24 months study period by descriptive statistical methods.
    End point values
    24 months of treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    19
    29
    Units: Number of
    32
    32
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Comprehensive assessments of any apparent toxicity experienced by the subject will be performed throughout the course of the study from the time of subject’s signature of informed consent.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    CTCAE
    Dictionary version
    4
    Reporting groups
    Reporting group title
    Adverse Event
    Reporting group description
    An adverse event is defined as any untoward medical occurrence in the form of signs, symptoms, abnormal laboratory findings, or diseases that emerges or worsens relative to baseline (i.e. present at the initial study visit) during a clinical study with an Investigational Medicinal Product, regardless of causal relationship and even if no Investigational Medicinal Product has been administered.

    Serious adverse events
    Adverse Event
    Total subjects affected by serious adverse events
         subjects affected / exposed
    7 / 30 (23.33%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Injury, poisoning and procedural complications
    Ankle fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Chest pain
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Atrial fibrillation
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Headache
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Influenza
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastric ulcer
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Erysipelas
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Adverse Event
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    23 / 30 (76.67%)
    Vascular disorders
    Hypotension
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Hypertension
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    General disorders and administration site conditions
    Dehydration
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Polyneuropathy
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    General disorders and administration site conditions,other; Cold feet, discomfort
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Respiratory, thoracic and mediastinal disorders
    Snoring
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Pneumothorax
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Psychiatric disorders
    Depression
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Injury, poisoning and procedural complications
    Fracture
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Cardiac disorders
    Atrial fibrillation
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Edema
    alternative assessment type: Systematic
         subjects affected / exposed
    6 / 30 (20.00%)
         occurrences all number
    6
    Dyspnea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Nervous system disorders
    Syncope
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Frontotemporal dementia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Dizziness
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Parkinson's disease
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Blood and lymphatic system disorders
    Anemia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Eye disorders
    cataract surgery
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Vitreous opacities
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Vitreous hemorrhage
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastrointestinal disorders
    Constipation
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Diarrhoea
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Gastritis
    alternative assessment type: Systematic
         subjects affected / exposed
    3 / 30 (10.00%)
         occurrences all number
    3
    Nausea
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Dyspepsia
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Hepatobiliary disorders
    Liver function test increased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Skin and subcutaneous tissue disorders
    Eczema
    Additional description: Eczema
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Skin lesion
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Renal and urinary disorders
    Creatinine renal clearance decreased
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2
    Urinary retention
    Additional description: Urinary retention
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Urinary tract infection
    Additional description: Urinary tract infection
    alternative assessment type: Systematic
         subjects affected / exposed
    5 / 30 (16.67%)
         occurrences all number
    5
    Infections and infestations
    Sinuitis
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1
    Infection
    alternative assessment type: Systematic
         subjects affected / exposed
    2 / 30 (6.67%)
         occurrences all number
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    19 Jun 2018
    Prolongation of the study with 2 years.

    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.
    Due to regulatory issue with licence with study medication there were several patients that could not fulfill the study.
    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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