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

    Summary
    EudraCT number
    		 2011-000776-34
    Trial protocol
    		 SE  
    Global end of trial date
    31 Dec 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Jun 2019
    First version publication date
    02 Jun 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    DFNS01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Umea University
    Sponsor organisation address
    Department of Medicine and Public health, Umea, Sweden,
    Public contact
    Ole B Suhr, Department of Medicine and Public Health, Umea University, ole.suhr@umu.se
    Scientific contact
    Ole B Suhr, Department of Medicine and Public Health, Umea University, ole.suhr@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
    05 May 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Dec 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Dec 2014
    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.
    Protection of trial subjects
    Safety follow-up: At 1, 3, 6, 9, 12 months and thereafter every 6 months blood samples were analysed for: B-Hb, blood platelets, s-creatinine, liver enzymes (ASAT and ALAT, s-bilirubin and ALP), S-proBNP. Yearly neurological examination.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jul 2011
    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: 54
    Worldwide total number of subjects
    54
    EEA total number of subjects
    54
    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)
    18
    From 65 to 84 years
    36
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 54 patients were included at three sites; Umeå, Piteå and Skellefteå hospitals. The study population was patients with transthyretin amyloidosis.

    Pre-assignment
    Screening details
    		 Inclusion criteria: - biopsy and genetically proven systemic transthyretin amyloidosis caused by a TTR gene mutation. The amyloid shall be proven to be of transthyretin type and the fibril composition settled. - age 18 years and above. - negative pregnancy test and contraception for sexually active women of childbearing potential.

    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 treatment with Diflunisal
    Arm description
    		 500 mg per os, Daily.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Diflunisal
    Investigational medicinal product code
    ATC code N02BA11, CAS no 22494-42-4
    Other name
    Pharmaceutical forms
    Film-coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg per os daily

    Number of subjects in period 1
    		24 months treatment with Diflunisal
    Started
    54
    Completed
    17
    Not completed
    37
         Adverse event, serious fatal
    1
         Consent withdrawn by subject
    2
         Physician decision
    2
         Adverse event, non-fatal
    6
         Liver transplant
    9
         Lost to follow-up
    1
         Change to other treatment
    1
         Study closure
    15

    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
    		 54 54
    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)
    		 18 18
        From 65-84 years
    		 36 36
        85 years and over
    		 0 0
    Gender categorical
    Units: Subjects
        Female
    		 14 14
        Male
    		 40 40

    End points

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    End points reporting groups
    Reporting group title
    24 months treatment with Diflunisal
    Reporting group description
    		 500 mg per os, Daily.

    Subject analysis set title
    18 months treatment with Diflunisal
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The 24 patients (out of 54) that completed 18 months treatment.

    Subject analysis set title
    12 months treatment with Diflunisal
    Subject analysis set type
    		 Sub-group analysis
    Subject analysis set description
    The 34 patients (out of 54) that completed 12 months of treatment.

    Primary: Changes in the Kumamoto scale

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    End point title
    		 Changes in the Kumamoto scale [1]
    End point description
    End point type
    Primary
    End point timeframe
    After 12, 18 and 24 months treatment.
    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: There is no comparison between treatment groups. Non-parametric statistical methods were used and p-values <0.05 were considered statistically significant.
    End point values
    		 24 months treatment with Diflunisal 18 months treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    17
    24
    34
    Units: score
    17
    24
    34
    No statistical analyses for this end point

    Secondary: Changes in nutritional status

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    End point title
    		 Changes in nutritional status
    End point description
    End point type
    Secondary
    End point timeframe
    After 12, 18 and 24 months of treatment.
    End point values
    		 24 months treatment with Diflunisal 18 months treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    17
    24
    34
    Units: mBMI
        number (not applicable)
    17
    24
    34
    No statistical analyses for this end point

    Secondary: Neurological impairment

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    End point title
    		 Neurological impairment
    End point description
    End point type
    Secondary
    End point timeframe
    After 12, 18, 24 months of treatment.
    End point values
    		 24 months treatment with Diflunisal 18 months treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    17
    24
    34
    Units: PND score
    17
    24
    34
    No statistical analyses for this end point

    Secondary: Cardiac impairment

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    End point title
    		 Cardiac impairment
    End point description
    Measured by ECG measurements of septal thickness and by proBNP in blood samples.
    End point type
    Secondary
    End point timeframe
    After 12, 18 and 24 months of treatment.
    End point values
    		 24 months treatment with Diflunisal 18 months treatment with Diflunisal 12 months treatment with Diflunisal
    Number of subjects analysed
    17
    24
    34
    Units: unit
    17
    24
    34
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Duration of the study
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTCAE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    Treatment with Diflunisal
    Reporting group description
    		 500 mg per os, Daily.

    Serious adverse events
    		 Treatment with Diflunisal
    Total subjects affected by serious adverse events
         subjects affected / exposed
    11 / 54 (20.37%)
         number of deaths (all causes)
    1
         number of deaths resulting from adverse events
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Pancreatic carcinoma
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Injury, poisoning and procedural complications
    Pelvic fracture
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Cardiac disorder - other, AV-block III
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Stroke
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorder - other, absence attack
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Malnutrition
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Appendicitis perforated
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pneumonia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Influenza
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Erysipelas
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Urinary tract infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Necrotising fasciitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Metabolism and nutrition disorders
    Dehydration
         subjects affected / exposed
    1 / 54 (1.85%)
         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
    		 Treatment with Diflunisal
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    32 / 54 (59.26%)
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Baker's cyst
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Vascular disorders
    Thrombophlebitis
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    General disorders and administration site conditions
    Edema limbs
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Cough
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Investigations
    Creatinine increased
         subjects affected / exposed
    5 / 54 (9.26%)
         occurrences all number
    5
    Investigations - other, Weight gain
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Investigations - other, increase in transaminase
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    2
    Injury, poisoning and procedural complications
    Fibula fracture
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac disorders - other, Increased pro-BNP
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Cardiac disorder - other, irregular heart rate
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Dizziness
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Syncope
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Dyspepsia
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Stomach pain
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Gastrointesinal disorder - other, blood in stool
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Diarrhoea
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Fecal incontinence
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Heartburn
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Eczema scaling
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    2
    Nail fragile
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Hair loss
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    3 / 54 (5.56%)
         occurrences all number
    3
    Infections and infestations - other, infected abrasion
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Cold
         subjects affected / exposed
    2 / 54 (3.70%)
         occurrences all number
    2
    Salmonella
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Infections and infestations- other, Shingles
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1
    Infection
         subjects affected / exposed
    1 / 54 (1.85%)
         occurrences all number
    1

    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.
    The study was closed due to publication of the Diflunisal study by Berk et. al., JAMA, Dec 2013.
    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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