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    Clinical Trial Results:
    A phase II multicenter pilot study of the safety and efficacy of Doxycycline/UrsoDeoxyCholicAcid on disease progression in ATTR amyloidosis

    Summary
    EudraCT number
    		 2011-005236-25
    Trial protocol
    		 SE  
    Global end of trial date
    16 Jun 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    02 Feb 2017
    First version publication date
    02 Feb 2017
    Other versions
    Summary report(s)
    		 DoxUrso - Clinical Study report - Assessment of Safety

    Trial information

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    Trial identification
    Sponsor protocol code
    Dox/Urso
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02016365
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Umeå University
    Sponsor organisation address
    Dept of Clinical Medicine and Public Health, Umeå, Sweden, 90187
    Public contact
    Ole B Suhr, Umeå University Dept of Clinical Medicine and Public Health, 0046 907851383, ole.suhr@medicin.umu.se
    Scientific contact
    Ole B Suhr, Umeå University Dept of Clinical Medicine and Public Health, 0046 907851383, ole.suhr@medicin.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
    04 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Jun 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    16 Jun 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective for this study is to evaluate the efficacy of doxycycline + ursodeoxycholic acid (UDCA) on disease progression in Transthyretin Amyloidosis (ATTR) subjects with cardiomyopathy with or without neuropathy.
    Protection of trial subjects
    The safety profile of doxycycline + ursodeoxycholic acid (UDCA) will be assessed through the recording, reporting and analysis of baseline medical conditions, physical examination findings including vital signs and laboratory tests. Monthly phone contacts will be performed for monitoring of the treatment safety. To assess the tolerability and safety of the treatment, blood work [e.g.complete blood count, creatinine and aspartate transaminase (AST), alkaline phosphatase(ALT)] for potential drug-related adverse events will be drawn at 1, 3, 6, 9, 12 and 18 month.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    06 Feb 2012
    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: 28
    Worldwide total number of subjects
    28
    EEA total number of subjects
    28
    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)
    4
    From 65 to 84 years
    24
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 Subjects which fulfills the inclusions criteria for the study: Adult males or non-pregnant, non-lactating females with ATTR amyloidosis, presenting cardiomyopathy with or without peripheral or autonomic neuropathy, having or not received a liver transplant 6-month prior to study entry.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    		 Yes
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Baseline
    Arm description
    		 Variables N (%) Median (Range) Age, years 72 (56-82) Male gender 20 (69) Hereditary ATTR 27 (96) Duration of disease (months) 24 (6-96) PNS involvement 26 (93) Kumamoto score 24 (0-59) Heart involvement 28 (100) LVW thickness, mm 19 (12-29) NTproBNP ng/l 2306 (326-34678) mBMI 947 (490-1447)
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ursodeoxycholic acid
    Investigational medicinal product code
    Other name
    Ursofalk
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg/day (500 mg +250mg orally) continuously.

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Doxyferm
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks.

    Number of subjects in period 1
    		Baseline
    Started
    28
    Completed
    28
    Period 2
    Period 2 title
    Overall period
    Is this the baseline period?
    		 No
    Allocation method
    Non-randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 Doxycycline and UDCA
    Arm description
    		 12 months of treatment with Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously) followed by 6 months of a withdrawal period.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ursodeoxycholic acid
    Investigational medicinal product code
    Other name
    Ursofalk
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    750 mg/day (500 mg +250mg orally) continuously.

    Investigational medicinal product name
    Doxycycline
    Investigational medicinal product code
    Other name
    Doxyferm
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    200 mg/day (100 mg twice daily, orally) for 4 weeks with a pause of 2 weeks.

    Number of subjects in period 2
    		Doxycycline and UDCA
    Started
    28
    Completed
    5
    Not completed
    23
         Adverse event, serious fatal
    3
         Physician decision
    2
         Consent withdrawn by subject
    6
         Adverse event, non-fatal
    6
         Lost to follow-up
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Variables N (%) Median (Range) Age, years 72 (56-82) Male gender 20 (69) Hereditary ATTR 27 (96) Duration of disease (months) 24 (6-96) PNS involvement 26 (93) Kumamoto score 24 (0-59) Heart involvement 28 (100) LVW thickness, mm 19 (12-29) NTproBNP ng/l 2306 (326-34678) mBMI 947 (490-1447)

    Reporting group values
    		 Baseline Total
    Number of subjects
    		 28 28
    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)
    		 4 4
        From 65-84 years
    		 24 24
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 72 (56 to 82) -
    Gender categorical
    Units: Subjects
        Female
    		 8 8
        Male
    		 20 20

    End points

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    End points reporting groups
    Reporting group title
    Baseline
    Reporting group description
    		 Variables N (%) Median (Range) Age, years 72 (56-82) Male gender 20 (69) Hereditary ATTR 27 (96) Duration of disease (months) 24 (6-96) PNS involvement 26 (93) Kumamoto score 24 (0-59) Heart involvement 28 (100) LVW thickness, mm 19 (12-29) NTproBNP ng/l 2306 (326-34678) mBMI 947 (490-1447)
    Reporting group title
    Doxycycline and UDCA
    Reporting group description
    		 12 months of treatment with Doxycycline (200 mg/day intermittently) and UDCA (750 mg/day continuously) followed by 6 months of a withdrawal period.

    Subject analysis set title
    Analysis for NT-pro BNP
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Analysis for NT-pro BNP

    Primary: The efficacy on serum N terminal proBNP (NT-proBNP)

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    End point title
    		 The efficacy on serum N terminal proBNP (NT-proBNP)
    End point description
    The efficacy on serum N terminal proBNP (NT-proBNP) [ Time Frame: At 12 month treatment ] [ Designated as safety issue: No ] The primary endpoint of the study is the response rate to doxycycline + UDCA treatment at month 12. A responder is an ATTR subject with: - a reduction of, or an increase in serum NT-proBNP concentration of less than 30% of pre-treatment level will be regarded as consistent with treatment efficacy
    End point type
    Primary
    End point timeframe
    At end of study period, 18 month
    End point values
    		 Baseline Doxycycline and UDCA Analysis for NT-pro BNP
    Number of subjects analysed
    28
    5
    5
    Units: NT proBNP>300 ng/L (at inclusion)
        number (not applicable)
    28
    5
    5
    Attachments
    		 Outcome of proBNP levels
    Statistical analysis title
    		 Analysis for NT-proBNP
    Comparison groups
    Baseline v Doxycycline and UDCA
    Number of subjects included in analysis
    33
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 = 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: mBMI reduction

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    End point title
    		 mBMI reduction
    End point description
    End point type
    Secondary
    End point timeframe
    12 month
    End point values
    Number of subjects analysed
    Units: mBMI-reduction of less than 10%
        number (not applicable)
    No statistical analyses for this end point

    Secondary: Increase of septum thickness

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    End point title
    		 Increase of septum thickness
    End point description
    End point type
    Secondary
    End point timeframe
    At end of study period, 18 month
    End point values
    Number of subjects analysed
    Units: less than or equal 2 mm
        number (not applicable)
    No statistical analyses for this end point

    Secondary: Neurologic Kumamoto Scale

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    End point title
    		 Neurologic Kumamoto Scale
    End point description
    End point type
    Secondary
    End point timeframe
    At end of study period, 18 month
    End point values
    Number of subjects analysed
    Units: change from baseline Kumamoto Scale
        number (not applicable)
    No statistical analyses for this end point

    Secondary: Tolerability and safety of the treatment

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    End point title
    		 Tolerability and safety of the treatment
    End point description
    Assesment of the tolerability and safety of the treatment, i.e. monitoring and recording all adverse events (AEs) and serious adverse events (SAEs), and the regularly scheduled monitoring of hematology, blood chemistry, physical examinations, and blood pressure over 12 months and 18 months.
    End point type
    Secondary
    End point timeframe
    At end of study period, 18 month
    End point values
    Number of subjects analysed
    Units: No of patients with AE, SAE etc.
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events are registered from the time point when the study participants sign the informed consent until their last visit at 18 month.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 CTC AE
    Dictionary version
    4.0
    Reporting groups
    Reporting group title
    All patients
    Reporting group description
    		 -

    Serious adverse events
    		 All patients
    Total subjects affected by serious adverse events
         subjects affected / exposed
    12 / 28 (42.86%)
         number of deaths (all causes)
    3
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Fracture rib
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Wrist fracture
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Vascular disorders
    Hematoma
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Cardiac disorders
    Heart failure
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 2
    Heart failure aggrevated
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    Stroke
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Sudden death NOS
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Skin and subcutaneous tissue disorders
    Skin ulceration
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    Musculoskeletal and connective tissue disorders
    Musculoskeletal and connective tissue disorder - other, vertebral compression
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    Infections and infestations - other, chills
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Sepsis
         subjects affected / exposed
    1 / 28 (3.57%)
         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
    		 All patients
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 28 (89.29%)
    Investigations
    Creatinine increased
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Vascular disorders
    Flushing
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Cardiac disorders
    Cardiac disorders - other, right bundel branch block
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nervous system disorders
    Depressed level of consciousness
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Memory impairment
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Paraesthesia
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    4
    Syncope
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Edema limbs
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Fatigue
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    General disorders and administration site conditions - other, thirst
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Eye disorders
    Cataract
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastrointestinal disorders
    Abdominal pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Constipation
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Diarrhoea
         subjects affected / exposed
    5 / 28 (17.86%)
         occurrences all number
    5
    Dry mouth
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Dysphagia
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Gastroesophageal reflux
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Hernia inguinal
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Nausea
         subjects affected / exposed
    5 / 28 (17.86%)
         occurrences all number
    7
    Stomach pain
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Tooth discoloration
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Vomiting
         subjects affected / exposed
    3 / 28 (10.71%)
         occurrences all number
    3
    Respiratory, thoracic and mediastinal disorders
    Dyspnoea
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Skin and subcutaneous tissue disorders
    Photosensitivity
         subjects affected / exposed
    7 / 28 (25.00%)
         occurrences all number
    7
    Pruritus
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Rash
         subjects affected / exposed
    4 / 28 (14.29%)
         occurrences all number
    4
    Skin and subcutaneous tissue - other blisters
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Renal and urinary disorders
    Haematuria
         subjects affected / exposed
    5 / 28 (17.86%)
         occurrences all number
    5
    Urinary frequency
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Urinary tract infection
         subjects affected / exposed
    2 / 28 (7.14%)
         occurrences all number
    2
    Urine discolouration
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders - other, muscle cramps
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Musculoskeletal and connective tissue disorders - other, stiffness hand
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Infections and infestations
    Infection and infestations - other cold
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Infection viral
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    1
    Mucosal infection mouth
         subjects affected / exposed
    1 / 28 (3.57%)
         occurrences all number
    2
    Wound infection
         subjects affected / exposed
    1 / 28 (3.57%)
         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 has extreme high drop out rate that was caused by treatment failure, side effects and voluntary dropouts, which may indicate lack of efficacy of the treatment.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/28042702
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